Antimicrobial Therapy in Veterinary Medicine

Chapter 11. Peptide Antibiotics: Polymyxins, Glycopeptides, Bacitracin, and Fosfomycin 195

C. difficile causes toxic enteritis in horses and com- Jackson MW, et al. 1994. Administration of vancomycin for
panion animals, reported isolates are susceptible to treatment of ascending bacterial cholangiohepatitis in a
metronidazole. cat. J Am Vet Med Assoc 204:602.

There are few reports of the clinical use of vancomy- Johnsen PJ, et al. 2011. Retrospective evidence for a biological
cin in veterinary medicine. The decision to use vanco- cost of vancomycin resistance determinants in the absence
mycin to treat a highly resistant pathogen in a veterinary of glycopeptide selective pressures. J Antimicrob Chemother
patient should only be made after consideration of the 66:608.
health risks to in-contact humans and other animals. An
effective infection control program is mandatory for Joosten U, et al. 2005. Effectiveness of hydroxyapatite-
such cases. Vancomycin therapy resolved clinical signs vancomycin bone cement in the treatment of Staphylo-
of cholangiohepatitis in cats, but did not necessarily coccus aureus induced chronic osteomyelitis. Biomaterials
produce a microbiological cure (Jackson et al., 1994; 26:5251.
Pressel et al., 2005). Practitioners have erroneously
administered oral vancomycin in the treatment of sys- Liu SJ, et al. 2002. In vivo release of vancomycin from biode-
temic infections in dogs (Weese, 2008). Vancomycin has gradable beads. J Biomed Mater Res 63:807.
been administered IV alone or in combination with an
aminoglycoside, to treat methicillin-resistant staphylo- Orsini JA, et al. 1992. Vancomycin kinetics in plasma and
coccal and enterococcal infections in horses (Orsini synovial fluid following intravenous administration in
et al., 2005). Vancomycin AIPMMA beads were used in horses. J Vet Pharmacol Ther 15:351.
conjunction with systemic vancomycin therapy at 6mg/kg
IV every 8 hours in a post-surgical infection from a Orsini JA, et al. 2005. Vancomycin for the treatment of
methicillin-resistant Staphylococcus epidermidis in a methicillin-resistant staphylococcal and enterococcal
horse (Trostle et al., 2001). infections in 15 horses. Can J Vet Res 69:278.

Bibliography Pressel MA, et al. 2005. Vancomycin for multi-drug resistant
Enterococcus faecium cholangiohepatitis in a cat. J Feline
Aarestrup FM, et al. 2001. Effect of abolishment of the use of Med Surg 7:317.
antimicrobial agents for growth promotion on occurrence
of antimicrobial resistance in fecal enterococci from food Ramos S, et al. 2012. Genetic characterisation of antibiotic
animals in Denmark. Antimicrob Agents Chemother resistance and virulence factors in vanA-containing
45:2054. enterococci from cattle, sheep and pigs subsequent to the
discontinuation of the use of avoparcin. Vet J 193:301.
Atilla A, et al. 2010. In vitro elution of amikacin and vanco-
mycin from impregnated plaster of Paris beads. Vet Surg Rubio-Martinez L, et al. 2005. Medullary plasma pharmacoki-
39:715. netics of vancomycin after intravenous and intraosseous
perfusion of the proximal phalanx in horses. Vet Surg 34:618.
Craig WA. 2003. Basic pharmacodynamics of antibacterials
with clinical applications to the use of beta-lactams, glyco- Rubio-Martinez LM, et al. 2005. Evaluation of safety and
peptides, and linezolid. Infect Dis Clin North Am 17:479. pharmacokinetics of vancomycin after intravenous
regional limb perfusion in horses. Am J Vet Res 66:2107.
Freitas AR, et al. 2011. Human and swine hosts share
vancomycin-resistant Enterococcus faecium CC17 and Thomas LA, et al. 2011. In vitro elution and antibacterial
CC5 and Enterococcus faecalis CC2 clonal clusters harbor- activity of clindamycin, amikacin, and vancomycin from
ing Tn1546 on indistinguishable plasmids. J Clin Microbiol R-gel polymer. Vet Surg 40:774.
49:925.
Trostle SS, et al. 2001. Treatment of methicillin-resistant
Ghosh A, et al. 2011. Dogs leaving the ICU carry a very large Staphylococcus epidermidis infection following repair of an
multi-drug resistant enterococcal population with capacity ulnar fracture and humeroradial joint luxation in a horse.
for biofilm formation and horizontal gene transfer. PLoS J Am Vet Med Assoc 218:554.
One 6:e22451.
Weese JS. 2008. Issues regarding the use of vancomycin in
Ghosh A, et al. 2012. Resident cats in small animal veterinary companion animals. J Am Vet Med Assoc 233:565.
hospitals carry multi-drug resistant enterococci and are
likely involved in cross-contamination of the hospital Witte W. 2004. Glycopeptide resistant Staphylococcus. J Vet
environment. Front Microbiol 3:62. Med B Infect Dis Vet Public Health 51:370.

Zaghlol HA, et al. 1988. Single- and multiple-dose pharma-
cokinetics of intravenously administered vancomycin in
dogs. Am J Vet Res 49:1637.

Teicoplanin

Teicoplanin has a molecular structure similar to that of

vancomycin and is also a derivative of an actinomycete.

It is a complex of five closely related antibiotics.

Teicoplanin has activity similar to and slightly greater

than vancomycin, being restricted also in activity to

Gram-positive bacteria. It has excellent activity against

196 Section II. Classes of Antimicrobial Agents

S. aureus (including methicillin-resistant strains) and Teicoplanin is used in human medicine for the treat-
against streptococci (in which it is more active than van- ment of serious infections caused by Gram-positive bac-
comycin), L. monocytogenes, C. difficile, C. perfringens, teria where a bactericidal drug is needed, where there is
and other Gram-positive bacteria. Enterococcus faecalis resistance to first line drugs, or where synergism with an
are somewhat less susceptible than other cocci. Nocardia aminoglycoside for broad-spectrum or enhanced activ-
are resistant to teicoplanin. Susceptible organisms are ity is required. Uses include septicemia, endocarditis,
those with an MIC ≤4 μmg/ml. Activity in vitro is more bone and joint infections, and cystitis caused by multire-
affected by test conditions than the activity of vancomy- sistant enterococci. Use in veterinary medicine has been
cin. Like vancomycin, the 24-hour AUC:MIC correlates limited. In 19 sheep treated with a single IM dose, teico-
with efficacy (Craig, 2003). planin was clinically and microbiologically effective
against mastitis caused by strains of S. aureus, coagulase-
Also like vancomycin, development of resistance to negative staphylococci and S. agalactiae. No adverse
teicoplanin is uncommon and these drugs have been reactions were observed. Teicoplanin (40 mg/day IM)
regarded as resistance-resistant. Nevertheless, VanA was effective in the treatment of an encrusted cystitis
resistance (causing cross-resistance to teicoplanin) caused by Corynebacterium urealyticum in a dog after
occurs in enterococci and resistance may develop in treatment with rifampin failed (Gomez et al., 1995).
coagulase-negative staphylococci, either as a result of
selection of mutants with progressive increases in MIC Bibliography
occurring in bacteria during treatment or, less com-
monly, by plasmid-mediated mechanisms. Craig WA. 2003. Basic pharmacodynamics of antibacterials
with clinical applications to the use of beta-lactams, glyco-
In humans, teicoplanin is not absorbed after oral peptides, and linezolid. Infect Dis Clin North Am 17:479.
administration. Absorption after IM injection is excel-
lent and the drug distributes widely into tissues in extra- Gomez A, et al. 1995. An encrusted cystitis caused by
cellular fluid. The elimination half-life is remarkably Corynebacterium urealyticum in a dog. Aust Vet J 72:72.
prolonged in humans, between 45 and 70 hours after IV
injection. Penetration into cerebrospinal fluid is poor Naccari C, et al. 2009. Pharmacokinetics and efficacy of
because of high molecular weight and poor lipid solubil- teicoplanin against intramammary infections in sheep. Vet
ity. Elimination is almost entirely renal. Pharmacokinetic Rec 165:19.
information is only available for sheep (Naccari et al.,
2009). In sheep given an IV dose of 6 mg/kg, teicoplanin Avoparcin
was characterized by a low volume of distribution and a
plasma elimination half-life of 5 hours. With IM injec- Avoparcin was used extensively as an antibiotic growth
tion, the bioavailability was 100% and “flip-flop” kinet- promoter in poultry and swine in Europe. The recogni-
ics occurred as evidenced by an increase in plasma tion that it selected for vancomycin-resistant enterococci
elimination to 9 hours. (VRE) in animals, and VRE contaminated a high propor-
tion of meat products derived from these animals, led to
Teicoplanin is synergistic with aminoglycosides its withdrawal from use in Europe (Casewell et al., 2003).
against some Gram-positive cocci, including penicillin- Avoparcin was not used in animal agriculture in North
tolerant enterococci, is indifferent or additive with America. With the avoparacin ban in 1995, there was an
rifampin, and may be synergistic with imipenem against immediate decrease in VRE isolated from poultry, but not
Gram-positive cocci. in pigs until tylosin was also banned from feed use
(Aarestrup et al., 2001). However, VREs have continued
In humans, teicoplanin is usually well tolerated. to cause significant problems in human hospitals not only
Adverse effects reported, in order of frequency, include: in Europe but also in North America, where avoparcin
hypersensitivity skin reactions (rash, pruritus, urticaria), has never been used in animals. Recent studies conclude
pain (IM) or phlebitis (IV) at injection sites, and rarely that animal-associated VRE probably reflect the former
nephrotoxicity or ototoxicity (usually in patients also use of avoparcin in animal production in Europe, whereas
receiving aminoglycosides). Teicoplanin, unlike vanco- VRE in human-associated samples may be a result of
mycin, can be administered by rapid IV injection. No antimicrobial use in hospitals (Kuhn et al., 2005).
information on toxicity in domestic animals is available.

Chapter 11. Peptide Antibiotics: Polymyxins, Glycopeptides, Bacitracin, and Fosfomycin 197

Bibliography Bacitracin is administered orally in poultry and swine
in North America, as bacitracin methylene disalicylate
Aarestrup FM, et al. 2001. Effect of abolishment of the use or zinc bacitracin, for growth promotion and for pre-
of  antimicrobial agents for growth promotion on occur- vention and treatment of enteritis (Butaye et al., 2003).
rence of antimicrobial resistance in fecal enterococci from Bacitracin, along with other antibiotic growth promot-
food animals in Denmark. Antimicrob Agents Chemother ers, has been banned for use in the European Union
45:2054. since 2006 (Castanon, 2007). Necrotic enteritis caused
by C. perfringens in chickens is prevented by the addi-
Casewell M, et al. 2003. The European ban on growth- tion of bacitracin at doses of 55–110 ppm to the feed.
promoting antibiotics and emerging consequences for Incorporation in feed may prevent proliferative adeno-
human and animal health. J Antimicrob Chemother 52:159. matosis in swine although Lawsonia intracellularis is
resistant in vitro (Kyriakis et al., 1996). Zinc bacitracin
Kuhn I, et al. 2005. Occurrence and relatedness of vancomy- was used in the treatment of colitis induced by tetracy-
cin-resistant enterococci in animals, humans, and the cline-contaminated sweet feed in a herd of horses (Keir
environment in different European regions. Appl Environ et al., 1999).
Microbiol 71:5383.

Bacitracin

Bacitracin is a polypeptide product of Bacillus subtilis. Bibliography
Bacitracin was first discovered in 1943 and named after
the Bacillus that was isolated from wound of a 7-year- Butaye P, et al. 2003. Antimicrobial growth promoters used in
old American girl named Margaret Tracey. It inhibits animal feed: effects of less well known antibiotics on gram-
the formation of bacterial cell-wall peptidoglycan by positive bacteria. Clin Microbiol Rev 16:175.
complexing directly with the pyrophosphate carrier and
inhibiting the dephosphorylation reaction required for Castanon JI. 2007. History of the use of antibiotic as growth
its regeneration. It is bactericidal to Gram-positive promoters in European poultry feeds. Poult Sci 86:2466.
bacteria but has little activity against Gram-negative
organisms. Resistance develops slowly. One unit of Jacob SE, et al. 2004. From road rash to top allergen in a flash:
bacitracin = 26 μg of the USP standard. bacitracin. Dermatol Surg 30:521.

Because bacitracin is highly nephrotoxic after paren- Keir AA, et al. 1999. Outbreak of acute colitis on a horse farm
teral administration, it is generally only used orally for a associated with tetracycline-contaminated sweet feed. Can
local effect or topically in the treatment of superficial Vet J 40:718.
infections of the skin and mucosal surfaces, particularly
where activity against Gram-positive bacteria is required. Keller RL, et al. 2005. Bacterial isolates and antimicrobial
Bacitracin is not absorbed from the gastrointestinal tract, susceptibilities in equine bacterial ulcerative keratitis
so no residues are found in meat when the product is (1993–2004). Equine Vet J 37:207.
administered orally. Because beta-lactam antibiotics are
potent contact sensitizers, they are not administered top- Kyriakis SC, et al. 1996. Clinical evaluation of in-feed zinc
ically; bacitracin replaces them for Gram-positive cover- bacitracin for the control of porcine intestinal adenomato-
age in topical products. However, allergic reactions and sis in growing/fattening pigs. Vet Rec 138:489.
fatal anaphylaxis have been described in humans (Jacob
and James, 2004). Bacitracin is often combined with neo- Fosfomycin
mycin and polymyxin B for broad-spectrum activity in
treating minor skin wounds or bacterial keratitis. While Fosfomycin (L-[cis]-1,2 epoxypropyl phosphonic acid)
frequently used as a first line treatment in horses, a is a phosphoenolpyruvate analogue that irreversibly
review of equine bacterial keratitis found only 64% of inhibits pyruvyl transferase, the enzyme catalyzing the
S.  zooepidemicus isolates were sensitive to bacitracin, first step of peptidoglycan biosynthesis. It is produced
suggesting that previous triple antibiotic therapy encour- by various Streptomyces spp. It is available for human use
ages antimicrobial resistance (Keller and Hendrix, 2005). as fosfomycin tromethamine, as a single oral dose treat-
ment for urinary tract infections. In some countries out-
side of North America, fosfomycin calcium for oral use
and fosfomycin disodium for intravenous use are avail-
able. It has a broad spectrum of activity against a wide

198 Section II. Classes of Antimicrobial Agents

range of Gram-positive and Gram-negative bacteria. It and only 1 was resistant to fosfomycin (MIC ≥ 256;
is highly active against Gram-positive pathogens such as Hubka and Boothe, 2011). For multidrug-resistant
Staphylococcus aureus and Enterococcus, and against clinical isolates, 97.2% were evaluated as susceptible. All
Gram-negative bacteria such as P. aeruginosa and isolates exhibiting extended-spectrum beta-lactamase
Klebsiella pneumonia (Michalopoulos et al., 2011). Its production were susceptible to fosfomycin. While the
unique mechanism of action may provide a synergistic availability of an oral formulation is attractive for admin-
effect to other classes of antibiotics including beta- istration to dogs and cats, further studies are needed,
lactams, aminoglycosides, and fluoroquinolones. Oral particularly regarding nephrotoxicity in cats, before fos-
fosfomycin is mainly used in the treatment of urinary fomycin can be recommended for clinical use. Oral fos-
tract infections, particularly those caused by Escherichia fomycin was also efficacious in the control of
coli and Enterococcus faecalis (Falagas et al., 2010). experimental E. coli infection in broiler chickens
Fosfomycin is considered a time-dependent antimicro- (Fernandez et al., 1998), but because of its value in treat-
bial. Activity is reduced by alkaline pH and the presence ing multidrug resistant bacteria in humans, fosfomycin is
of glucose, sodium chloride or phosphates in culture unlikely to be approved for use in food animal species.
media. Resistance, which can be chromosomal or
plasmid-mediated, is uncommon. There is no cross- Bibliography
resistance with other antibacterial drugs.
Falagas ME, et al. 2010b. Fosfomycin for the treatment of
Fosfomycin has a low volume of distribution (0.2 L/kg) multidrug-resistant, including extended-spectrum beta-
and minimal protein binding. Bioavailability of fosfo- lactamase producing, Enterobacteriaceae infections: a
mycin disodium from SC and IM injections is variable systematic review. Lancet Infect Dis 10:43.
(38–85%). Oral bioavailability in dogs is only 30%.
Fosfomycin is rapidly eliminated, with a plasma half-life Fernandez A, et al. 1998. Efficacy of phosphomycin in the
of 1.23 hours in horses, 1.3 hours in dogs, 2.2 hours in control of Escherichia coli infection of broiler chickens. Res
cattle, 2 hours in broilers, and 1.5 hours in swine Vet Sci 65:201.
(Gutierrez et al., 2010; Gutierrez et al., 2008; Soraci et al.,
2011; Sumano et al., 2007; Zozaya et al., 2008). Fukata T, et al. 2008. Acute renal insufficiency in cats after
fosfomycin administration. Vet Rec 163:337.
Studies performed in rats showed that fosfomycin had
a protective effect against nephrotoxicity due to amino- Gutierrez L, et al. 2010. Pharmacokinetics of disodium
glycosides, by inhibiting aminoglycoside-induced hista- fosfomycin in broilers and dose strategies to comply with
mine release from mast cell destruction (Michalopoulos its pharmacodynamics versus Escherichia coli. Poult Sci
et al., 2011). However, cats given fosfomycin for only 3 89:2106.
days developed acute renal insufficiency, while no
adverse effects were seen in dogs (Fukata et al., 2008; Gutierrez OL, et al. 2008. Pharmacokinetics of disodium-
Gutierrez et al., 2008). fosfomycin in mongrel dogs. Res Vet Sci 85:156.

There is increasing interest in the use of fosfomycin in Hubka P, et al. 2011. In vitro susceptibility of canine and
the treatment multidrug-resistant Gram-negative infec- feline Escherichia coli to fosfomycin. Vet Microbiol
tions in veterinary species. Therapeutic options for 149:277.
E. coli infections in dogs or cats are limited with the
increase in resistance to third-generation cephalospor- Michalopoulos AS, et al. 2011. The revival of fosfomycin. Int
ins and fluoroquinolones. In a study where 275 clinical J Infect Dis 15:e732.
(from dogs and cats, predominantly urinary tract iso-
lates) and experimental isolates were tested, 272 (98.9%) Soraci AL, et al. 2011. Disodium-fosfomycin pharmacokinet-
were susceptible (MIC ≤ 2 μg/ml), 2 were intermediate, ics and bioavailability in post weaning piglets. Res Vet Sci
90:498.

Sumano LH, et al. 2007. Intravenous and intramuscular phar-
macokinetics of a single-daily dose of disodium-fosfomycin
in cattle, administered for 3 days. J Vet Pharmacol Ther
30:49.

Zozaya DH, et al. 2008. Pharmacokinetics of a single bolus
intravenous, intramuscular and subcutaneous dose of dis-
odium fosfomycin in horses. J Vet Pharmacol Ther 31:321.

Lincosamides, Pleuromutilins, 12
and Streptogramins

Steeve Giguère

Lincosamides, pleuromutilins, and streptogramins are streptogramins, and chloramphenicol. Lincosamides
structurally distinct but share many common proper- can be bactericidal or bacteriostatic, depending on the
ties. They are basic compounds characterized by high drug concentration, bacterial species, and inoculum of
lipid solubility, wide distribution in the body, and capac- bacteria. Many Gram-negative bacteria are resistant
ity to penetrate cellular barriers. In addition, along with because of impermeability and methylation of the ribo-
macrolides, they share overlapping binding sites on the somal binding site of lincosamides.
50S subunit of the ribosome.
Antimicrobial Activity
Lincosamides: Lincomycin, Clindamycin,
and Pirlimycin Lincosamides are moderate-spectrum antimicrobial
drugs. Clindamycin is several times more active than
Chemistry lincomycin, especially against anaerobes and S. aureus.
Lincosamides are active against Gram-positive bacteria,
Lincomycin, the parent compound, was isolated in 1963 anaerobic bacteria, and some mycoplasma (Table 12.1).
from the fermentation of Streptomyces spp. Many modi- They lack activity against most Gram-negative bacteria.
fications of the lincomycin molecule have been devel-
oped in an attempt to produce an improved antibiotic. t Good susceptibility (MIC ≤ 2.0 mg/ml): Gram-positive
Of these, only clindamycin showed distinct advantages aerobes: Bacillus spp., Corynebacterium spp.,
over lincomycin. Pirlimycin, a clindamycin analog, Erysipelothrix rhusiopathiae, staphylococci, strepto-
is  also approved as an intramammary infusion for cocci (but not enterococci). Gram-negative bacteria:
the treatment of mastitis in cattle. The chemical struc- Campylobacter jejuni. Anaerobes: many anaerobes
ture of  lincomycin and clindamycin are displayed in including Actinomyces spp., Bacteroides spp. (including
Figure 12.1. B. fragilis), and C. perfringens (but not all other
Clostridium spp.). Fusobacterium spp., and anaerobic
Mechanism of Action cocci are particularly susceptible to clindamycin.
Activity of clindamycin against anaerobes is similar
The lincosamides inhibit protein synthesis by binding to chloramphenicol, and metronidazole. Clindamycin
to  the 50S ribosomal subunit and inhibiting peptidyl has activity against some protozoa such as Toxoplasma
transferases. The ribosomal binding sites are the same gondii and Plasmodium falciparum. It is has some
as  or closely related to those that bind macrolides, activity against Pneumocyctis jiroveci. The breakpoint

Antimicrobial Therapy in Veterinary Medicine, Fifth Edition. Edited by Steeve Giguère, John F. Prescott and Patricia M. Dowling.
© 2013 John Wiley & Sons, Inc. Published 2013 by John Wiley & Sons, Inc.

199

200 Section II. Classes of Antimicrobial Agents

CH3 CH3 elements and can be located on the bacterial chromo-
CH R some or on plasmids.

N This cross-resistance is of two types: (1) constitutive
resistance (MLSBc), where bacteria show high-level
C NH CH resistance to all MLSB antibiotics; and (2) dissociated
inducible cross-resistance (MLSBi), in which bacteria
H3CH2CH2C O HO O resistant to macrolides but initially fully susceptible to
OH clindamycin rapidly develop resistance to lincosamides
S CH3 when exposed to macrolides. Constitutive resistant
Lincomycin R=OH OH mutants are rapidly selected from the inducible strains
Clindamycin R=CI during treatment with either lincosamides or mac-
rolides. Constitutive resistance may be more common
Figure 12.1. Chemical structure of lincomycin and among bacteria isolated from food animals fed tylosin
clindamycin. or virginiamycin as growth promoters. MLSBc isolates
are readily recognized during in vitro susceptibility test-
set by the CLSI for susceptibility to clindamycin in ing as being resistant to both macrolides and clindamy-
Staphylococcus spp. isolates from dogs with skin and cin. However, MLSBi resistance is not detected by
soft tissue infection is ≤ 0.5 μg/ml. The breakpoint set standard in vitro susceptibility testing methods. Such
by the CLSI for susceptibility to pirlimycin in Staphy- isolates appear resistant to macrolides but susceptible
lococcus aureus and Streptococcus spp. isolates from to  clindamycin under standard testing conditions. As
cows with mastitis is ≤ 2 μg/ml. a  result, isolates that are resistant to macrolides but
t Resistant (MIC ≥ 4 mg/ml): All aerobic Gram-negative susceptible to clindamycin should also be tested for
rods, Nocardia spp., and Mycobacterium spp. Linco- methylase-mediated clindamycin resistance by an addi-
samides are also inactive against Enterococcus faecalis tional assay, the D-zone test. Isolates that demonstrate
and E. faecium. inducible clindamycin resistance based on a D-zone test
should be reported as clindamycin resistant (Lewis and
Resistance Jorgensen, 2005).

Resistance can develop to the lincosamides alone but Other mechanisms of resistance to lincosamides
more commonly cross-resistance occurs among mac- involve enzymatic inactivation and active efflux of the
rolides, lincosamides, and streptogramin group B anti- drug from the periplasmic space. Inactivation is medi-
biotics (MLSB resistance). In some instances, ated by nucleotidyltransferases encoded by lnu(A-F).
cross-resistance may also include ketolides (phenotype
referred to as MLSK resistance) and oxazolidinones Pharmacokinetic Properties
(MSLKO) antimicrobials. Cross-resistance is not always
present and its occurrence depends on the mechanism Lincosamides are basic compounds with pKa values of
of cross-resistance. about 7.6. They have high lipid solubility and conse-
quently large apparent volumes of distribution. They
Lincosamide-resistant strains generally have the are well absorbed from the intestine of non-herbivores
MLSB resistance phenotype. This can occur by sponta- and eliminated mainly by hepatic metabolism, although
neous point mutations in the genes coding for the ribo- about 20% is eliminated in active form in the urine.
somal peptidyltransferase loop. However, in most Clindamycin is hydrolyzed in the liver in to at least
strains, resistance is the result of methylation of adenine 7  metabolites. All metabolites but one are devoid of
residues in the 23S ribosomal RNA of the 50S ribosomal antibacterial activity. Tissue concentrations consist-
subunit, which prevents drug binding to the target ently exceed serum concentrations by several times
site.  The rRNA methylases are encoded by a series of because of passage across cell membranes. Because of
structurally related erythromycin-resistant methylase the lincosamide’s basic character, ion trapping also
(erm) genes. The erm genes are acquired through mobile occurs in tissues, such as the udder and prostate where
pH is lower than blood. Extensive binding to plasma

Chapter 12. Lincosamides, Pleuromutilins, and Streptogramins 201

Table 12.1. In vitro activity (MIC90) of lincosamides and pleuromutilins antibiotics
(μg/ml) against selected bacterial and mycoplasmal pathogens.

Organisms Clindamycin/ Pirlimycin Tiamulin Valnemulin
Lincomycina

Gram-positive aerobes

Arcanobacterium pyogenes < 0.06* − 0.03 −

Erysipelothrix rushiopathiae 1 − 4−

Rhodococcus equi 4 − 64 −

Staphylococcus aureus 0.25 1 0.03 −

Streptococcus equi 16 8 0.5 −

S. agalactiae 4 0.5 − −

S. dysgalactiae 16 1 − −

S. uberis > 32 8 − −

Enterococcus faecalis 16 2 > 32 −

Gram-negative aerobes

Actinobacillus pleuropneumoniae > 32a − 8–

Histophilus somni − − 2−

Mannheimia haemolytica − − 4−

Pasteurella multocida > 25 − 32 −

Escherichia coli > 32 > 32 32 −

Klebsiella spp. > 32 > 32 > 128 −

Enterobacter spp. > 32 > 32 > 32 −

Anaerobes

Dichelobacter nodosus 0.25 − − −

Bacteroides fragilis 0.5 0.06 − −

Fusobacterium necrophorum 0.5 0.5 0.016 −

Brachyspira hyodysenteriae 4 − 0.25 0.06

Brachyspira pilosicoli 8 − 0.5 0.5

Clostridium perfringens 4 0.5 − −

Mycoplasma

Mycoplasma bovis > 256 − 0.25 −

M. hyorhinis 2a − 0.25 −

M. hyopneumoniae 0.12a − 0.25 < 0.005

M. hyosynoviae − − 0.06 < 0.005

M. mycoides mycoides − − 0.5 −

Ureaplasma spp. − − 0.06 −

Leptospira spp. 0.2 − 4 −

Lawsonia intracellularis 32a − 4 2

a MIC values indicated bya are for lincomycin, the others are for clindamycin.
* Some reports show resistance to clindamycin

proteins and relatively rapid elimination prevent Drug Interactions
concentrations in cerebrospinal fluid (CSF) from
exceeding 20% of serum concentrations. Clindamycin Combination with spectinomycin appears to give mar-
achieves therapeutic concentrations in bone, although ginally enhanced activity against mycoplasmas in vitro.
levels are relatively low, around 10–30% of serum Clindamycin is commonly combined with an aminogly-
concentrations. coside or a fluoroquinolone in human medicine to treat
or prevent mixed aerobic-anaerobic bacterial infections,

202 Section II. Classes of Antimicrobial Agents

particularly those associated with intestinal spillage Lincomycin is relatively non-toxic to dogs and cats.
into  the peritoneum. The combination generally has Anorexia, vomiting, and diarrhea have sometimes
additive or synergistic effects in vitro against a wide occurred especially with oral use. Administration of
range of bacteria. Clindamycin has synergistic effects clindamycin capsules without food or water has
with metronidazole against B. fragilis but only additive resulted in esophagitis and esophageal ulcerations
effects with trimethoprim-sulfamethoxazole combina- sometimes progressing to stricture in cats (Beatty et
tion against common Gram-negative or Gram-positive al., 2007). Anaphylactic shock has been reported after
aerobes. Combination with macrolides or chloram- IM injection. Because of their peripheral neuromus-
phenicol is antagonistic in vitro. cular blocking and cardiac depressive effects, lincosa-
mides should not be given with anesthetics or by
Toxicity and Adverse Effects rapid IV injection. Clindamycin given IM is very
painful.
The major toxic effect of the lincosamides is their ability
to cause serious and fatal diarrhea in humans, horses, Administration and Dosage
rabbits, and other herbivores.
Usual dosages are shown in Table 12.2.
In humans, mild diarrhea follows the use of lincosa- After oral administration to monogastric animals,
mides in up to 10% of patients, but in some (0–2.5%
of  those treated) this may become severe, resulting in lincomycin is generally absorbed well and clindamycin
pseudomembranous colitis with profound shock, dehy- is absorbed almost completely. Food significantly
dration, and death. The disease is caused by the rapid reduces absorption of both drugs, especially lincomycin.
colonic growth of lincosamide-resistant Clostridium Complete absorption occurs from IM injection sites.
difficile through destruction of competing anaerobic Clindamycin palmitate, available as a syrup for oral
microflora of the colon. Treatment with vancomycin or administration, is rapidly hydrolyzed in the intestine
metronidazole is often successful. Less serious toxic before absorption. The drug is also available in capsules
effects in humans include depressed neuromuscular as the hydrochloride for oral administration and as the
transmission and post-anesthetic paralysis, depression phosphate for IM, SC, or IV injection. The SC route is
of cardiac muscle after rapid IV injection, mild liver superior to the IM route in terms of local tolerance and
damage, drug rashes, and urticaria. serum concentrations. Lincomycin is available as the
hydrochloride for PO, IM, and IV administration. The
In cattle, oral administration of lincomycin at concen- dosage should be reduced in patients with hepatic
trations as low as 7.5 parts/million (ppm) in feed has insufficiency.
resulted in inappetence, diarrhea, ketosis, and decreased
milk production. Inadvertent contamination of feed Table 12.2. Usual dosages of lincosamides and
with 8–10 ppm of lincomycin and 40 ppm of metronida- pleuromutilins in animals.
zole caused some affected cows to develop severe diar-
rhea and to lose consciousness. In horses, lincosamides Species Dosage Route Interval (h)
administered by parenteral or oral route can cause Drug (mg/kg)
severe enterocolitis, which may be fatal. In one inadvert-
ent mixing of lincomycin in horse feed, a dose of 0.5 mg/ Dog/cat Clindamycin 5–11 PO, IV, IM, SC 12–24
kg caused an outbreak of diarrhea in which one horse Ruminantsa Lincomycin 10–20 PO, IV, IM 12–24
died. Anal swelling, diarrhea, irritable behavior and skin Swine Lincomycin 5–10 IM 12–24
reddening have been reported in pigs but these signs are Tiamulin 20 IM 24
generally self-limiting within 5–8 days. Lincomycin 10 IM 24
Tiamulin 10–15 IM 24
Lincosamides are highly toxic to rabbits, guinea pigs, 8–23 PO, feed 24
and hamsters. Concentrations as low as 8 ppm acciden- Valnemulin 1.5–4 PO, feed 24
tally added to feed have been followed by severe and
fatal cecocolitis in rabbits. In rabbits the effect is the aThese drugs are not approved for use in ruminants and have few, if any,
result of bacterial overgrowth in the large bowel of indications.
C. difficile or Clostridium spiroforme.

Chapter 12. Lincosamides, Pleuromutilins, and Streptogramins 203

Clinical Applications and was almost as effective as the same dose given on
each of 3 days (Venning et al., 1990). Lincomycin (8 g/L)
Lincosamides are used in the treatment of staphylococ- administered as a spray once daily for 5 days was effec-
cal infections (dermatitis, osteomyelitis) caused by peni- tive in the control of papillomatous digital dermatitis in
cillin G–resistant organisms, for other Gram-positive cattle (Shearer and Elliott, 1998). The combination has
aerobic infections in penicillin-sensitive individuals, also been used in the treatment of rams to prevent urea-
and in the treatment of anaerobic infections. In general, plasma contamination of semen (Marcus et al., 1994).
clindamycin is preferred to lincomycin. Clindamycin The successful treatment of arthritis and pedal osteomy-
has excellent activity against anaerobes, equivalent to elitis usually associated with A. pyogenes with parenteral
alternatives such as cefoxitin, chloramphenicol, and lincomycin was also reported (Plenderleith 1988). Oral
metronidazole. Clindamycin may be combined with an administration of lincomycin to ewes at a dosage of
aminoglycoside or a fluoroquinolone in the treatment of 225 mg/day resulted in severe enterocolitis leading to
mixed anaerobic infections. Clindamycin may be pref- death in 2,000 of 3,000 exposed animals (Bulgin 1988).
erable to penicillin G or ampicillin in the treatment of
streptococcal toxic shock syndrome, since it better Swine
inhibits superantigen synthesis (Sriskadan et al., 1997). Lincomycin is largely used in pigs to control dysentery
Lincosamides penetrate well into the prostate and eyes. and mycoplasma infections; control of erysipelas and
There are some doubts about the efficacy in vivo of clin- streptococcal infections may be incidental benefits to
damycin in the treatment of toxoplasmosis, although incorporating the drug in feed for the principal pur-
combination with pyrimethamine may enhance efficacy. poses. Lincomycin is used in feed or water (33 mg/L) to
Clindamycin may be useful in treating Pneumocystis treat (100 ppm feed) or prevent (40 ppm feed) swine
jiroveci infection, in combination with primaquine. In dysentery. Lincomycin can also be administered at
swine, lincomycin is used extensively in the prevention 11 mg/kg IM for 3–7 days. A drawback has been failure
and treatment of dysentery and sometimes for myco- to sterilize B. hyodysenteriae, so that withdrawal of drug
plasma infections. is followed by recrudescence of infection. Nevertheless,
whole herd medication has apparently eradicated swine
Cattle, Sheep, and Goats dysentery from closed herds even in some cases with
There are no formulations of lincosamides labeled for infection caused by apparently resistant organisms.
systemic use in ruminants. The major indication for the Lincomycin is effective in reducing losses from
use of lincosamides in cattle is intramammary infusion Mycoplasma hyosynoviae and Mycoplasma hyorhinis.
in cases of mastitis. Pirlimycin is labeled and commer- Pleuromutilins are considerably more effective than lin-
cially available for that purpose. Intramammary pirlimy- comycin in control of swine dysentery and mycoplasma
cin been proven effective against mastitis caused by infections in swine. Lincomycin delivered in the drink-
Staphylococcus species such as Staphylococcus aureus ing water has also been shown to be effective for the
and Streptococcus species such as Streptococcus dysgalac- treatment of proliferative enteropathy both in a field
tiae and Streptococcus uberis (Gillespie et al., 2002; study and following experimental infection (Bradford
Olivier et al., 2004). Prepartum treatment of dairy heif- et al., 2004; Alexopoulos et al., 2006). Lincomycin may
ers with pirlimycin reduces the prevalence of early lacta- be given in feed, water, or by IM injection.
tion mastitis caused by coagulase-negative staphylococci
(Middleton et al., 2005). Horses
Lincomycin and clindamycin have been used experi-
There are few, if any, indications for the other lincosa- mentally to induce enterocolitis in horses. These drugs
mides in ruminants because of the availability of should not be used in horses, although there are rare
approved alternatives. Subconjunctival injection of reports of apparently successful use in the treatment of
clindamycin was effective in the treatment of natu- osteomyelitis by IM injection without apparent adverse
rally  occurring infectious bovine keratoconjunctivitis effects.
(Senturk et al., 2007). A single IM injection of the com-
bination (5 mg/kg lincomycin, 10 mg/kg spectinomycin)
cured over 90% of sheep with acute or chronic foot rot

204 Section II. Classes of Antimicrobial Agents

Dogs and Cats et  al., 1995; Dubey et al., 2007). Clindamycin was also
Lincosamides are used in the treatment of abscesses, successful for the treatment of dogs experimentally
osteomyelitis, periodontal disease, and soft tissue or infected with Babesia gibsoni (Wulansari et al., 2003).
wound infections that involve Gram-positive cocci or Clindamycin in combination with diminazene and imi-
anaerobic bacteria. In experimentally induced Staphy- docarb was more effective at eradicating B. gibsoni in
lococcus aureus osteomyelitis in dogs, a dosage of 11 mg/kg naturally infected dogs than a combination of atovaquone
of clindamycin administered q 12 h for 28 days effec- and azithromycin (Lin et al., 2012)
tively resolved the infection. Dosage of 5.5 mg/kg q 12 h
was less effective. Clindamycin has been administered Poultry
at  low daily oral dosage in the successful prophylaxis Lincomycin-spectinomycin combination is adminis-
of recurrent staphylococcal skin infections. Field trials tered orally to young chickens for the control of
have demonstrated the 94–100% efficacy of single-daily mycoplasmal air sacculitis and complicated chronic res-
dosing with 11 mg/kg orally (average duration 45 days) piratory disease caused by M. gallisepticum and E. coli
in the treatment of deep pyoderma in dogs (Harvey Lincomycin has also been used in the control of necrotic
et  al., 1993; Scott et al., 1998). Lincomycin (22 mg/kg, enteritis caused by susceptible pathogens such as
q  12 h) orally is equally effective in the treatment of C. perfringens.
staphylococcal skin disease in dogs (Harvey et al., 1993).
Bibliography
In a study of experimental anaerobic infections in
dogs, clindamycin at 5.5 or 11 mg/kg administered twice Alexopoulos C, et al. 2006. First experience on the effect of
daily IM, was highly efficacious and gave better results in-feed lincomycin for the control of proliferative enter-
than lincomycin, 22 mg/kg twice daily. Clindamycin is opathy in growing pigs. J Vet Med A Physiol Pathol Clin
used effectively in the treatment of dental infections in Med 53:157.
dogs, when combined with dental surgery or cleaning
(Johnson et al., 1992). Anecdotally, its routine use in Beatty JA, et al. 2007. Suspected clindamycin-associated
periodontal surgery has been associated with problems oesophageal injury in cats: five cases. J Feline Med Surg
of salmonellosis in veterinary hospitals. Clindamycin is 8:412.
useful for prostatic infections caused by Gram-positive
bacteria. Dosing of 11 mg/kg once daily orally appears to Boothe DM, et al. 1996. Plasma disposition of clindamycin
be appropriate, but the same dose could be administered microbiological activity in cats after single oral doses of
twice daily in serious infections (e.g., osteomyelitis). clindamycin hydrochloride as either capsules or aqueous
solution. J Vet Pharm Ther 19:491.
Clindamycin has been used successfully in the treat-
ment of toxoplasmosis in a dog and in cats, although it Bradford JR, et al. 2004. Evaluation of lincomycin in drinking
was unsuccessful in treating feline chorioretinitis or water for treatment of induced porcine proliferative enter-
anterior uveitis in all cases. Clindamycin administered to opathy using a Swine challenge model. Vet Ther 5:239.
cats experimentally infected with toxoplasmosis did not
prevent ocular lesions and was associated with increased Brown SA, et al. 1990. Tissue concentrations of clindamycin
morbidity and mortality from hepatitis and interstitial after multiple oral doses in normal cats. J Vet Pharm Ther
pneumonia (Davidson et al., 1996). In contrast, clinda- 13:270.
mycin completely prevented shedding of T. gondii in
experimentally infected cats even after severe immuno- Bulgin MS. 1988. Losses related to the ingestion of lincomycin-
suppression (Malmasi et al., 2009). Combination with medicated feed in a range sheep flock. J Am Vet Med Assoc
pyrimethamine was less effective in long-term treatment 192:1083.
of toxoplasmic encephalitis in human patients than the
combination of pyrimethamine-sulfadiazine (Katlama Davidson MG, et al. 1996. Paradoxical effect of clindamycin
et al., 1996). Clindamycin was successful in resolving clini- in experimental acute toxoplasmosis in cats. Antimicrob
cal signs caused by Neosporum caninum in dogs although Agents Chemother 40:1352.
the pathogen was not necessarily eradicfated (Dubey
Dubey JP, et al. 1995. Canine cutaneous neosporosis: clinical
improvement with clindamycin. Vet Dermatol 6:37.

Dubey JP, et al. 2007. Neosporosis in Beagle dogs: clinical
signs, diagnosis, treatment, isolation and genetic charac-
terization of Neospora caninum. Vet Parasitol 149:158.

Gillespie BE, et al. 2002. Efficacy of extended pirlimycin
hydrochloride therapy for treatment of environmental
Streptococcus spp and Staphylococcus aureus intramam-
mary infections in lactating dairy cows. Vet Ther 3:373.

Chapter 12. Lincosamides, Pleuromutilins, and Streptogramins 205

Harvey RG, et al. 1993. A comparison of lincomycin hydro- Mechanism of Action
chloride and clindamycin hydrochloride in the treatment
of superficial pyoderma in dogs. Vet Rec 132:351. Pleuromutilin antibiotic derivatives inhibit protein syn-
thesis by binding to the 50S subunit of the bacteria.
Johnson LA, et al. 1992. Klinische wirksamkeit von clinda- Tiamulin and valnemulin are strong inhibitors of pepti-
mycin (Cleorobe) bei infektionen des zahn-, mund- under dyl transferase. They can bind concurrently with the
kieferbereiches des hundes. Prakt Tier 73:94. macrolide erythromycin but compete with the mac-
rolide carbomycim for binding to the ribosome (Poulsen
Katlama C, et al. 1996. Pyrimethamine-clindamycin vs. et al., 2001).
pyrimethamine-sulfadiazine as acute and long-term ther-
apy for toxoplasmic encephalitis in patients with AIDS. Antimicrobial Activity
Clin Infect Dis 22:268.
Tiamulin and valnemulin have outstanding activity
Lewis JS, Jorgensen JH. 2005. Inducible clindamycin resistance against anaerobic bacteria and mycoplasma (Table 12.1).
in  staphylococci: should clinicians and microbiologists be They are active against some Gram-positive aerobic
concerned. Clin Infect Dis 40:280. bacteria including Staphylococcus spp., A. pyogenes, and
some streptococci. Tiamulin is active against only a few
Lin EC, et al. 2012. The therapeutic efficacy of two antibabe- Gram-negative aerobic species and inactive against
sial strategies against Babesia gibsoni. Vet Parasitol 186:159. Enterobacteriaceae (Table 12.1) although subinhibitory
concentrations may reduce adhesive properties of enter-
Malmasi A, et al. 2009. Prevention of shedding and re-shedding otoxigenic E. coli (Larsen, 1988). Activity against anaer-
of Toxoplasma gondii oocysts in experimentally infected cats obic bacteria and mycoplasma is better than that of
treated with oral Clindamycin: a preliminary study. Zoonoses macrolide antibiotics. Swine respiratory pathogens with
Public Health 56:102. a MIC ≤ 8 μg/ml are considered susceptible and ≥ 32 μg/
ml are considered resistant to tiamulin. Valnemulin is
Marcus S, et al. 1994. Lincomycin and spectinomycin in the about twice as active as tiamulin against bacteria and
treatment of breeding rams with semen contaminated with over 30 times more active against swine mycoplasma in
ureaplasmas. Res Vet Sci 57:393. vitro (Aitken et al., 1999).

Middleton JR, et al. 2005. Effect of prepartum intramammary Resistance
treatment with pirlimycin hydrochloride on prevalence of
early first-lactation mastitis in dairy heifers. J Am Vet Med As with the macrolides, chromosomal mutation to
Assoc 227:1969. resistance of pleuromutilins emerges readily on in vitro
passage of bacteria in the presence of the drug. The rate
Oliver SP, et al. 2004. Influence of prepartum pirlimycin of emergence is significantly lower than with tylosin.
hydrochloride or penicillin-novobiocin therapy on masti- There is one-way cross-resistance with tylosin: myco-
tis in heifers during early lactation. J Dairy Sci 87:1727. plasma isolates resistant to tylosin have slightly increased
resistance to tiamulin, but mycoplasma isolates resistant
Scott DW, et al. 1998. Efficacy of clindamycin hydrochloride to tiamulin are completely resistant to tylosin. There is
capsules for the treatment of deep pyoderma due to isolate variation in bacterial cross-resistance with the
Staphylococcus intermedius infection in dogs. Can Vet J other macrolides and lincosamide antibiotics, which
39:753. may include modest increases in resistance to spectino-
mycin and chloramphenicol. Mutations at the peptidyl
Senturk S, et al. 2007. Evaluation of the clinical efficacy of transferase center associated with reduced susceptibility
subconjunctival injection of clindamycin in the treatment to tiamuline have been characterized in Brachyspira spp.
of naturally occurring infectious bovine keratoconjuncti- isolates (Pringle et al., 2004). A significant increase in
vitis. Vet Ophthalmol. 10(3):186. the MIC of tiamulin and valnemulin for Brachyspira
hyodysenteriae isolates over time has been documented
Sriskandan S, et al. 1997. Comparative effects of clindamycin (Lobova et al., 2004; Hidalgo et al., 2011).
and ampicillin on superantigenic activity of Streptococcus
pyogenes. J Antimicrob Chemother 40:275.

Venning CM, et al. 1990. Treatment of virulent foot rot with
lincomycin and spectinomycin. Aust Vet J 67:258.

Wulansari R, et al. 2003. Clindamycin in the treatment of
Babesia gibsoni infections in dogs. J Am Anim Hosp Assoc
39:558.

Pleuromutilins: Tiamulin and Valnemulin

Tiamulin and valnemulin are semisynthetic derivatives
of the naturally occurring diterpene antibiotic pleuro-
mutilin. Pleuromutilins have outstanding activity against
anaerobic bacteria and mycoplasma and are used almost
exclusively in animals, largely in swine.

206 Section II. Classes of Antimicrobial Agents

Pharmacokinetic Properties Intramuscular injection of certain preparations may
be irritating but formulations of tiamulin base in sesame
Tiamulin is used as the hydrogen fumarate in the oral oil are not. Intravenous injection of calves resulted in
preparation but as the tiamulin base in the parenteral severe neurotoxicity and death. Orally administered
product. Valnemulin is available as a hydrocloride pre- tiamulin is transiently unpalatable and irritating in
mix for medicated feed. Little information has been calves.
published on the pharmacokinetic characteristics of
pleuromutilins. Tiamulin is rapidly absorbed after oral Acute dermatitis with cutaneous erythema and
administration to pre-ruminant calves and has a half- intense pruritus has been described in pigs following
life of 25 minutes following parenteral administration. oral administration of tiamulin (Laperle, 1990), where it
Tiamulin is a lipophilic, weak organic base, with a pKa of was associated with poor hygiene and overcrowding. It
7.6. The drug penetrates cells well and is concentrated was suggested that metabolites of tiamulin in urine had
several-fold in milk. Concentration in other tissues is a directly irritant effect on the skin.
several times that in serum. The half-life in dogs after
IM administration was 4.7 hours, and serum concentra- Medication of pigs with valnemulin in the European
tions were higher and maintained for longer when the Union has resulted in adverse effects characterized by
drug was given by SC injection (Laber, 1988). Tiamulin inappetence, pyrexia, ataxia, and sometimes recum-
is almost completely absorbed after oral administration bency. The majority of cases occurred in Denmark and
in monogastric species but would be expected to be Sweden. In these countries, the incidence of these
inactivated by rumen flora if administered orally to adverse effects ranged from 0.03% to 1.8% of all pigs
ruminants. Administration of tiamulin to swine in med- treated. On some farms, up to one third of treated pigs
icated feed, rather than by direct oral administration, became affected with a mortality rate of 1%. An epide-
strongly decreases its rate and extent of absorption and miological study has suggested an association between
consequently serum concentrations. The bioavailability susceptibility to these adverse reactions and the Swedish
of valnemulin in pigs and in broiler chickens is around and Danish Landrace breed.
90%. Similar to what has been described for tiamulin,
valnemulin concentrations in the colonic content and Pleuromutilins should not be administered to horses
tissues exceed serum concentrations. Dosage recom- because of the potential danger for disruption of the
mendations are presented in Table 12.2. colonic microflora and predisposition to enterocolitis.

Drug Interactions Clinical Applications

Drug interactions have not been studied extensively but Tiamulin or valnemulin are used extensively in swine
are likely to be similar to those described for lincosa- against mycoplasma pneumonia, swine dysentery, and
mides and macrolides. Tiamulin and valnemulin have proliferative illeitis. Less commonly, tiamulin has been
been shown to interact with ionophores such as monen- used against leptospirosis, and to a lesser extent against
sin, salinomycin, lasalocide, and narasin. Animals bacterial pneumonia. Tiamulin is preferred over mac-
should not receive these products during at least 5 days rolides for many infections.
before or after treatment with pleuromutilins. Severe
growth depression, ataxia, paralysis or death may result Cattle, Sheep, and Goats
(Miller, 1986). Pleuromutilins are not approved for use in ruminants.
There are few reports of the use of tiamulin or valnemu-
Toxicity and Adverse Effects lin in cattle. Tiamulin has been used successfully to pre-
vent Mycoplasma bovis fibrinous polyarthritis and
Tiamulin should not be fed at therapeutic concentra- synovitis in veal calves after administration in milk at
tions with ionophores such as monensin, narasin, and 400 ppm for the fattening period (Keller et al., 1980). In
salinomycin to animals (pigs, poultry) because of the sheep, tiamulin had a beneficial effect on the course of
dose-dependent fatal effects of such combinations, field cases of infectious rickettsial keratoconjunctivitis
which results from tiamulin’s potent inducer-inhibiting (Konig, 1983). Ball and McCaughey (1986) found that a
activity against cytochrome P-450 in the liver. single SC injection of aqueous tiamulin eliminated urea-
plasma from the genital tract of 18 of 22 sheep.

Chapter 12. Lincosamides, Pleuromutilins, and Streptogramins 207

Valnemulin administered orally was effective in the outbreaks of respiratory disease in swine. The most
control of Mycoplasma bovis infections in calves under common pathogens isolated from affected pigs were
both experimental and field conditions. In one study, Actinobacillus pleuropneumoniae, Pasteurella multocida,
Valnemulin resulted in a more rapid reduction of clini- and Mycoplasma hyopneumoniae (Najiani et al., 2005).
cal scores and eliminated M. bovis from the lungs more Tiamulin has proved superior to tylosin in treating
effectively than enrofloxacin (Stipkovits et al., 2005). experimental mycoplasma and bacterial pneumonia in
Valnemulin topical spray has a similar efficacy as linco- swine (Hannan et al., 1982). Tiamulin has been used with
mycin in the treatment of digital dermatitis in cattle apparent success in eradicating A. pleuropneumoniae
(Laven and Hunt, 2001). infection from herds (Larsen et al., 1990) and also in
reducing lesions in pigs treated for chronic A. pleuropneu-
Swine moniae infection (Anderson and Williams, 1990).
Tiamulin is labeled in the United States as a growth
promoter and for the treatment of swine dysentery asso- Tiamulin fed at 200 ppm in feed for 10 days cured
ciated with B. hyodysenteriae and pneumonia due to chronic kidney carriage of experimental L. pomona
A.  pleuropneumoniae susceptible to tiamulin. It has infection. Tiamulin administered in drinking water
good activity against E. rhusiopathiae, Leptospira, and significantly reduced the effects of experimentally
streptococci and moderate activity against A. pleuropneu- induced S. suis type 2 infection (Chengappa et al., 1990).
moniae. Tiamulin is used in strategic medication in Tiamulin is effective in the prevention and treatment of
pig production to prevent and treat common infections. proliferative enteropathy (McOrist et al., 1996).
Its activity in vitro against M. hyopneumoniae requires
confirmation in vivo. Valnemulin is approved in the European Union for
the treatment and prevention of enzootic pneumonia
The drug is highly effective in preventing and treating (M. hyopneumoniae), swine dysentery (B. hyodysenteriae),
swine dysentery. Concentrations of 60 ppm in water for colonic spirochaetosis (B. pilosicoli) and proliferative
3–5 days apparently eradicated experimental infections; enteropathy (L. intracellularis) in pigs. Valnemulin has
relapses occurred when lower concentrations were used. been shown to be effective for the treatment or prevention
Tiamulin at 30 ppm in feed has prevented dysentery. of both experimentally induced and naturally acquired
Incorporation into water (45 ppm for 5 days, 60 ppm for infection with M. hyopneumoniae, B. hyodysenteriae, B.
3 days) effectively treated swine dysentery and was bet- pilosicoli and L. intracellularis (Burch, 2004b). Although
ter than tylosin (Pickles, 1982). A single IM dose of valnemulin significantly reduces lung lesions in cases
10–15 mg/kg has successfully treated clinical cases of of enzootic pneumonia, M. hyopneumoniae is not com-
dysentery (Burch et al., 1983). Tiamulin may be used to pletely eliminated.
eradicate swine dysentery from herds using a variety of
approaches. These have included daily injection of carri- Poultry
ers with 10 mg/kg IM for 5 consecutive days, combined Valnemulin and tiamulin in the drinking water have
with management changes and rodent control (Blaha been shown to be effective in the control of Mycoplasma
et al., 1987), or oral administration to grower pigs for gallisepticum infections (Jordan, 1998). Tiamulin was
10 days followed by carbadox for 42 days (Moore, 1990). also shown to be effective for the treatment of B. pilosicoli
infections (Stephens and Hampson, 2002).
Tiamulin has been effective in treating field cases of
enzootic pneumonia and other mycoplasma infections. Bibliography
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feed on its bioavailability in piglets. Vet Res 24:494.
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tinomycin against Mycoplasma gallisepticum. Avian Dis 42:738 lincomycin for the treatment of broiler breeders experimen-
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Laber G. 1988. Investigation of pharmacokinetic parameters Streptogramins
of tiamulin after intramuscular and subcutaneous admin-
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pristinamycin) or semisynthetic (quinupristin/dalfopris-
Laperle A. 1990. Dermatite aigue chez des porcs traités à la tin) cyclic peptides. The natural streptogramines are
tiamuline. Med Vet Quebec:20. produced as secondary metabolites by Streptomyces spp.
Streptogramins are unique among antibiotics since each
Larsen H, et al. 1990. Eradication of Actinobacillus pl euro- member of the class consists of at least two structurally
pneumoniae from a breeding herd. Int Pig Vet Soc 18. unrelated molecules: group A streptogramins (macrol-
actones) and group B streptogramins (cyclic hexadepsi-
Larsen JL. 1988. Effect of subinhibitory concentrations of peptides). Virginiamycin has been developed largely as a
tiamulin on the haemagglutinating properties of fimbriated growth promoter, but pristinamycin and quinupristin/
Escherichia coli. Res Vet Sci 45:134. dalfopristin have been developed for clinical use in
human medicine, the former for oral administration
Laven RA, Hunt H. 2001. Comparison of valnemulin and and the latter for parenteral use. Only virginiamycin has
lincomycin in the treatment of digital dermatitis by indi-
vidually applied topical spray. Vet Rec 149:302.

Lobova D, et al. 2004. Decreased susceptibility to tiamulin
and valnemulin among Czech isolates of Brachyspora
hyodysenteriae. J Med Microbiol 53:287.

Martineau GP, et al. 1980. Bronchopneumonie enzootique du
porc: Ameliorati on de l’index pulmonaire apres traitement
par la tiamuline. Ann Med Vet 124:281.

Chapter 12. Lincosamides, Pleuromutilins, and Streptogramins 209

been studied in veterinary species. New streptogramins Virginiamycin
with improved in vitro activity are currently being inves-
tigated (Eliopoulos et al., 2005). Virginiamycin is an antibiotic mixture of virginiamycin S
(group B) and virginiamycin M (group A), produced as a
Mechanism of Action fermentation product of Streptomyces virginiae. The drug
is mainly active against Gram-positive aerobic and anaer-
Streptogramins inhibit bacterial protein synthesis by obic bacteria (such as Clostridium perfringens). Most
undergoing strong irreversible binding to the 50S ribo- Gram-negative bacteria are resistant: Histophilus, Lawsonia
somal subunit. The group A and B streptogramins bind intracellularis, Leptospira spp., and B. hyodysenteriae are
to separate sites on the 50S subunit of the bacterial ribo- exceptions. Mycoplasma spp. are often susceptible.
some. Binding of group A streptogramins to the
ribosome induces a conformational change that increases There are few data available on the pharmacokinetic
affinity of the ribosome for group B compounds. Group properties of virginiamycin in animals. The drug is not
A streptogramins prevent peptide bond formation dur- absorbed after oral administration. It is safe if adminis-
ing the chain elongation step, while group B compo- tered orally. Virginiamycin is still used in some countries
nents cause the release of the incomplete peptide chains to promote growth in animals at the level of 5–20 ppm
from the 50S ribosomal subunit. The group B strepto- (chapter 22). The use of virginiamycin for this indication
gramins share an overlapping binding site with mac- was been banned by the European Union in 1999 because
rolides and lincosamides on the ribosome even tough of resistance in enterococcal isolates. It is administered
these antimicrobials are structurally unrelated to each to swine at 110 ppm in feed to control swine dysentery,
other. Individually, the A and B compounds are bacte- but results have sometimes been poor. The drug does not
riostatic, whereas in combination they are bactericidal. eradicate infection, and duration of treatment should
Their synergistic activity tends to reduce the emergence be  several weeks. Virginiamycin (Founderguard) has
of bacteria resistance to either drug. been used to control cecal fermentation and prevent
laminitis in horses fed high concentrate rations. Dietary
Resistance supplementation with virginiamycin may also lessen
some behavioral problems associated with management
Since group A and B streptogramins are chemically of stabled horses and the intake of grain.
unrelated and have different binding sites, the mecha-
nisms of resistance to these two compounds are differ- There is little information on the development and
ent. Resistance may be chromosomal or plasmid prevalence of resistance to virginiamycin. Studies of
mediated. The first and most common mechanism of C.  perfringens isolated from turkeys and pigs have not
resistance to streptogramins B is the acquisition of identified resistant isolates. In a recent study, horses
rRNA methylases encoded in the erythromycin-resistant receiving virginiamycin to prevent pasture-associated
methylase (erm) genes. These enzymes add one or two laminitis were not significantly more likely to shed
methyl groups to a single adenine in the 23S rRNA streptogramin-resistant E. faecium compared to non-
moity. This gives the host bacteria resistance to mac- exposed horses. However, the high frequency of resist-
rolides, lincosamides, and streptogramins B (MLSB) ance within both groups was alarming. Use of
antibiotics. The second and less common mechanism virginiamycin as a feed additive may result in the selec-
for resistance to streptogramins B is linearisation of the tion of resistant fecal enterococci with cross-resistance
hexadepsipeptide ring by specific lyases. to a related streptogramin antibiotic, quinupristin-
dalfopristin (Synercid), which has been used in human
Resistance to class A streptogramins is mediated by 2 medicine for the treatment of vancomycin-resistant
mechanisms. The first mechanism is active efflux due to enterococci and other infections (see below).
ABC transporter proteins. These proteins pump the
drug out of the cell or the cellular membrane, keeping Bibliography
intracellular concentrations low and allowing the ribo-
some to function. The second mechanism is inactiva- Eliopoulos GM, et al. 2005. In vitro activity of an oral strep-
tion of the drug by acetyltransferases. togramin antimicrobial, XRP2868, against gram-positive
bacteria. Antimicrob Agents Chemother 7:3034.

210 Section II. Classes of Antimicrobial Agents

Johnson KG, et al. 1998. Behavioural changes in stabled against some fastidious Gram-negative aerobes and
horses given nontherapeutic levels of virginiamycin. Gram-negative anaerobes. Gram-positive bacteria with
Equine Vet J 30:139. acquired resistance to macrolides and lincosamides com-
monly develop resistance to the streptogramin B rather
Menzies-Gow NJ, et al. 2011. Antibiotic resistance in faecal than to the A component of the combination. These
bacteria isolated from horses receiving virginiamycin features, as well as the properties of high susceptibility
for  the prevention of pasture-associated laminitis. Vet among Gram-positive bacteria, make this combination
Microbiol 152:424. of considerable interest in human medicine for the treat-
ment of susceptible multiresistant bacteria. Examples
Roberts MC. 2004. Resistance to macrolide, lincosamide, include methicillin-resistant S. aureus (MRSA) and
streptogramin, ketolide, and oxazolidinone antibiotics. penicillin- or erythromycin-resistant pyogenic strepto-
Mol Biotechnol 28:47. cocci. An important feature is the activity of the combina-
tion against vancomycin-resistant Enterococcus faecium.
Ronne H, Jensen JEC. 1992. Virginiamycin susceptibility of Since virginiamycin is used extensively as a growth
Serpulina hyodysenteriae in vitro and in vivo. Vet Rec promoter in animals, there is considerable concern that
131:239. continued use of this drug in food-producing animals
may interfere with the efficacy of the combination for the
Thal LA, Zervos MJ. 1999. Occurrence and epidemiology treatment of vancomycin-resistant enterococcal infec-
of  resistance to virginiamycin and streptogramins. tions in people. Quinupristin/dalfopristin is also active in
J Antimicrob Chemother 43:171. vitro against Streptococcus pneumoniae, Neisseria spp.,
Mycoplasma spp., Legionella spp., Haemoplilus spp., and
Welton LA, et al. 1998. Antimicrobial resistance in entero- Chlamydia spp. Among the anaerobes, Clostridium per-
cocci isolated from turkey flocks fed virginiamycin. fringens and C. difficile are the most susceptible. The
Antimicrob Agents Chemother 42:705. combination is also active against many other anaerobes
including Fusobacterium spp. and peptostreptococci.
Pristinamycin and Quinupristin/Dalfopristin
Bibliography
Pristinamycin was isolated from Streptomyces pristi-
naespiralis. Pristinamycin has 2 components: 30–40% is Brown J, Freeman BB. 2004. Combining quinupristin/
pristinamycin IA (group B) and 60–70% is pristinamy- dalfopristin with other agents for resistant infections. Ann
cin IIA (group A). Pristinamycin has been used as Pharmacother 38:677.
an oral antibiotic for humans in Europe since 1968. It
is  active against Gram-positive bacteria, especially Finch RG. 1996. Antibacterial activity of quinupristin/
Staphylococcus and Streptococcus spp., and a few Gram- dalfopristin. Drugs Suppl 1:31.
negative bacteria such as Haemophilus, Neisseria, and
Legionella spp. It is also active against Mycoplasma spp. Lentino JR, et al. 2008. New antimicrobial agents as therapy for
resistant gram-positive cocci. Eur J Clin Microbiol Infect
Quinupristin/dalfopristin consists of a mixture of Dis 27:3.
semisynthetic water-soluble derivatives of pristinamy-
cins IA (quinupristin) and IIA (dalfopristin). Its water Pechere J-C. 1996. Streptogramins. A unique class of antibi-
solubility allows IV administration, making it the first otics. Drugs 51 Suppl 1:13.
injectable streptogramins available for clinical use. The
combination has a wide distribution in most tissues. In Van den Bogaard AE, et al. 1997. High prevalence of coloniza-
humans, both components are highly protein bound and tion with vancomycin- and pristinamycin-resistant entero-
are cleared rapidly from plasma via biliary excretion by cocci in healthy humans and pigs in The Netherlands: is
hepatic conjugaison. Phlebitis at the site of infusion is the  addition of antibiotics to animal feeds to blame?
the most common adverse effect. Arthralgia and myal- J Antimicrob Chemother 40:454.
gia, both of which are reversible upon discontinuation
of therapy, occur in up to 5% of treated patients.

Quinupristin/dalfopristin is bactericidal against
many Gram-positive bacteria, with selective activity

Macrolides, Azalides, and Ketolides 13

Steeve Giguère

Macrolides (macro meaning large and olide meaning natural origin (spiramycin, josamycin, midecamycin)
lactone) are characterized by having a central 12- to and semisynthetic derivatives (tilmicosin, tildipirosin).
16-membered lactone ring that has few or no double
bonds and no nitrogen atoms to which two or As a class, the macrolides exhibit broad distribution
more  sugar  moieties are attached. The efficacy of this in tissues and, in the case of some of the newer drugs,
group of drugs  against important human pathogens, prolonged half-lives. They also have excellent activity
including Campylobacter, Chlamydia, Legionella, and against many important bacterial pathogens of animals.
Mycobacterium species, has resulted in development of The macrolides are also known for their intracellular
semisynthetic members with increased antibacterial accumulation within phagocytes. However, the precise
activity, improved pharmacokinetic parameters, and pharmacodynamic relationships between intracellular
reduced adverse reactions. concentrations and bacterial killing remain to be
defined.
The macrolides are classified according to the number
of atoms comprising the lactone ring e.g., 12-, 13-, Mechanism of Action
14-,  15-, or 16- (Figure  13.1). The 12-member ring
macrolides are no longer used in clinical practice. Macrolides inhibit protein synthesis by reversibly bind-
Tulathromycin, a semisynthetic macrolide approved for ing to 50S subunits of the ribosome. They inhibit the
use in swine and cattle, consists of an equilibrated regio- transpeptidation and translocation process, causing pre-
isomeric mixture of a 13-membered ring (10%) and a mature detachment of incomplete polypeptide chains.
15-membered ring (90%). The unique structural feature Their binding sites on the 23S rRNA of the 50S riboso-
of this antimicrobial places it in a novel category of mac- mal subunit overlap with that of lincosamides, strepto-
rolides termed triamilides. The 14-member ring group gramins, ketolides and oxazolidinones but are different
contains compounds of natural origin (erythromycin from those of chloramphenicol. Macrolides are gener-
and oleandomycin) and semisynthetic derivatives ally bacteriostatic agents but they may be bactericidal at
(clarithromycin, roxithromycin, dirithromycin). The high concentrations and against a low inoculum of some
15-member ring is represented by azithromycin, gam- highly susceptible bacteria.
ithromycin, and one isomer of tulathromycin. The
15-membered ring macrolides are termed azalides as Resistance
they have a nitrogen atom in the lactone ring. The
16-member group also contains both compounds of Three different mechanisms account for most bacterial
resistance to the action of macrolides: (1) rRNA meth-
ylation; (2) active efflux; and (3) enzymatic inactivation.

Antimicrobial Therapy in Veterinary Medicine, Fifth Edition. Edited by Steeve Giguère, John F. Prescott and Patricia M. Dowling.
© 2013 John Wiley & Sons, Inc. Published 2013 by John Wiley & Sons, Inc.

211

212 Section II. Classes of Antimicrobial Agents
Macrolide antibiotics

13-Membered ring 14-Membered ring 15-Membered ring 16-Membered ring

Semisynthetic Natural Semisynthetic Semisynthetic Natural Semisynthetic

Tulathromycin(10%) Erythromycin Clarithromycin Azithromycin Spiramycin Tilmicosin
Oleandomycin Roxithromycin Gamithromycin Tylosin Tildipirosin
Dirithromycin Tulathromycin (90%) Josamycin Tylvalosin
Fluorithromycin Midecamycin Miokamycin
Rokitamycin

Figure 13.1. Classification of macrolide antimicrobials according to the size of the macrocyclic lactone ring.

rRNA methylation and active efflux are the mechanisms macrolides, lincosamides, and streptogramins. The
responsible in the majority of resistant isolates. Most efflux genes have been found in a variety of Gram-
macrolide resistance genes are associated with mobile positive and Gram-negative bacteria.
elements and thus have the capacity to spread between
strains, species, and bacterial ecosystem. The third and less common mechanism of resistance
is due to enzymatic inactivation. There are currently 2
rRNA methylation, encoded by erythromycin- esterase and 6 phosphorylase inactivating enzymes
resistant methylase (erm) genes, results in cross-resistance known to be involved in macrolide resistance. The clini-
to  the macrolides, lincosamides, and streptogramin B cal significance of this last mechanism has not been
(MSLB resistance). To date, 35 different rRNA methyl- clearly established.
ases have been characterized. These methylase genes are
widely distributed in both Gram-positive and Gram- Between 1% and 4% of macrolide-resistant Gram-
negative bacteria, and can be located on plasmids or positive bacteria do not carry any of the known acquired
transposons. The expression of erm genes can be consti- macrolide resistance genes described above. These
tutive or inducible. Constitutive resistance occurs when isolates typically have mutations in their rRNA genes
the methylase enzyme is inherently produced. Inducible and/or ribosomal protein genes, which confer macrolide
resistance occurs when enzyme induction is effected by resistance.
exposure of the microorganism to 14- or 15-member
ring macrolides, but not to 16-member ring macrolides. Drug Interactions

Efflux of macrolide antimicrobial agents is mediated There have been relatively few studies of the interactions
by members of the ATP binding cassette family of pro- of macrolide antibiotics with other antimicrobial drugs.
teins or by major facilitator superfamily transporters. Combinations of erythromycin with other macrolides,
These proteins pump antimicrobial agents out of the cell lincosamides, and chloramphenicol are antagonistic in
or cellular membrane, thereby allowing the bacterial vitro. Erythromycin has been used alone or with an ami-
ribosomes to function again. Currently, 20 different noglycoside to prevent or treat peritonitis after intestinal
efflux genes have been recognized. Some of these genes spillage, but it is not as effective as clindamycin or
confer resistance to 14- and 15-member ring macrolides metronidazole in combination with an aminoglycoside.
while not interfering with susceptibility to 16-member Combination of a macrolide and a fluoroquinolone
ring macrolides, ketolides, lincosamides, and strep- or  aminoglycoside may be synergistic, antagonistic, or
togramin B. Other efflux genes lead to a variety of indifferent depending on the microorganism studied.
different resistance patterns including resistance to all Combination of a macrolide with rifampin is synergistic
against Rhodococcus equi.

Chapter 13. Macrolides, Azalides, and Ketolides 213

Erythromycin and many other macrolides lead to motilin receptor agonists. These effects have been dem-
inactivation of the cytochrome P450 enzyme complex. onstrated for erythromycin in horses (Lester et al., 1998)
Thus, concurrent administration of erythromycin and dogs (Cowles et al., 2000), and for erythromycin,
increases concentrations of drugs that are primarily tylosin, and tilmicosin in cattle (Nouri and Constable,
dependent upon CYP3A enzyme metabolism such as 2007).
theophylline, midazolam, carbamazepine, omeprazole,
and ranitidine. Clarithromycin and roxithromycin have Bibliography
lower affinity for the P450 system than erythromycin
and other classic macrolides (except spiramycin). Altenburg J, et al. 2011. Immunomodulatory effects of
Azithromycin, dirithromycin and spiramycin do not macrolide antibiotics—part 1: biological mechanisms.
interact with the hepatic cytochrome P450 system and Respiration 81:67.
are not associated with the drug interactions observed
with erythromycin and other macrolides. Cowles VE, et al. 2000. Effect of novel motilide ABT-229
versus erythromycin and cisapride on gastric emptying in
Anti-inflammatory and Prokinetic Activities dogs. J Pharmacol Exp Ther 293:1106.
of Macrolides
Fischer CD, et al. 2011. Anti-inflammatory benefits of
Macrolides have immunomodulatory effects that are antibiotic-induced neutrophil apoptosis: tulathromycin
beneficial for humans suffering from many inflamma- induces caspase-3-dependent neutrophil programmed cell
tory pulmonary diseases such as cystic fibrosis, idiopatic death and inhibits NF-kappaB signaling and CXCL8 tran-
bronchiectasis, and chronic obstructive pulmonary dis- scription. Antimicrob Agents Chemother 55:338.
ease (Friedlander and Albert, 2010). These effects are
likely independent of the antibacterial activity of these Friedlander AL, Albert RK. 2010. Chronic macrolide therapy
drugs. Erythromycin, azithromycin, clarithromycin, in inflammatory airways diseases. Chest 138:1202.
and roxithromycin inhibit chemotaxis and infiltration
of neutrophils into the airway and, subsequently, Lakritz J, et al. 1997. Effect of treatment with erythromycin
decrease mucus secretion. The mechanisms of action for on bronchoalveolar lavage fluid cell populations in foals.
the anti-inflammatory properties of the macrolides are Am J Vet Res 58:56.
multifactorial and still under investigation (Altenburg
et al., 2011). Macrolides inhibit the production of many Lakritz J, et al. 2002. Tilmicosin reduces lipopolysaccharide-
proinflammatory cytokines including interleukin (IL)- stimulated bovine alveolar macrophage prostaglandin E(2)
1, IL-6, IL-8, and tumor necrosis factor-alpha by sup- production via a mechanism involving phospholipases.
pressing the transcription factor nuclear factor-kappa B Vet Ther 3:7.
or activator protein-1. Macrolides also inhibit formation
of leukotriene B4, which attracts neutrophils and inhibit Lester GD, et al. 1998. Effect of erythromycin lactobionate
superoxide anion release by neutrophils that may be on myoelectric activity of ileum, cecum, and right ventral
present in the airway. In addition, macrolides block for- colon, and cecal emptying of radiolabeled markers in clini-
mation of adhesion molecules necessary for neutrophil cally normal ponies. Am J Vet Res 59:328.
migration. Recent studies suggest an effect of macrolide
on adaptive immunity as well. These anti-inflammatory Nerland EM, et al. 2005. Effects of oral administration of
and immunomodulatory effects have been described in tilmicosin on pulmonary inflammation in piglets experi-
foals receiving erythromycin (Lakritz et al., 1997), and mentally infected with Actinobacillus pleuropneumoniae.
in cattle and pigs administered tilmicosin or tulathro- Am J Vet Res 66:100.
mycin (Fischer et al., 2011; Lakritz et al., 2002; Nerland
et al., 2005). Nouri M, Constable PD. 2007. Effect of parenteral administra-
tion of erythromycin, tilmicosin, and tylosin on abomasal
Macrolides with 14- or 16-member ring have pro- emptying rate in suckling calves. Am J Vet Res 68:1392.
kinetic effects on the gastrointestinal tract by acting as
Macrolides Approved for Veterinary Use:
Erythromycin, Tylosin, Spiramycin,
Tilmicosin, Tulathromycin, Gamithromycin,
Tildipirosin, and Tylvalosin

Erythromycin

Erythromycins are produced as a complex of six compo-
nents (A to F) by Saccharopolyspora erythraea (formerly
Streptomyces erythraeus). Only erythromycin A has been

214 Section II. Classes of Antimicrobial Agents

O Erythromycin O Clarithromycin Azithromycin
N
HO OH HO O
OH O OH O HO OH
OH O

O O N O O N O O N
O O OH O O OH O O OH

O O O
O O O

OH OH HN OH

HO OH

Tilmicosin O OH O
O O
N N

HO OH O O OH
O O
O Tulathromycin
OO O O N O isomer A
O O OH OH
HO

N
H

Figure 13.2. Structural formulas of macrolides. Courtesy of Jérôme del Castillo.

developed for clinical use. Erythromycin has a macrocy- Bordetella spp., Haemophilus spp., Legionella spp.,
clic lactone nucleus to which ketones and amino sugars Ehrlichia spp., Pasteurella spp.
are attached (Figure  13.2). Its base has a pKa of 8.8, is t Resistant (MIC ≥ 8 μg/ml) bacteria include all
poorly soluble in water, and is unstable in gastric acid. Enterobacteriaceae, Pseudomonas spp., Nocardia spp.,
Mycobacterium spp. (other than M. kansasii), and
Antimicrobial Activity some Mycoplasma spp.

t Good susceptibility (MIC ≤ 0.5 μg/ml) is generally seen Pharmacokinetic Properties
in the following Gram-positive aerobes: Bacillus spp., The erythromycin base is highly susceptible to degrada-
Corynebacterium spp., Erysipelothrix rhusiopathiae, tion from gastric acids. To circumvent this, orally
Listeria spp., Rhodococcus equi, staphylococci, strepto- administered erythromycin requires an enteric coating.
cocci. Among Gram-negative aerobes: Actinobacillus However, this leads to considerable individual variation
spp., Brucella spp.; Campylobacter spp., Leptospira spp. in absorption. Erythromycin is available for oral admin-
Anaerobic bacteria: Actinomyces spp., Bacteroides istration as the free base, the stearate or phosphate salts,
spp.  (except B. fragilis), Clostridium spp., some and as estolate or ethylsuccinate esters. The stearate is
Fusobacterium spp., and anaerobic cocci. Erythromycin hydrolyzed in the intestine to the active base, and the
is also active against some Chlamydia/Chlamydophila ethylsuccinate and estolate esters are absorbed as such
spp. and Mycoplasma spp. (Table 13.1). and hydrolyzed in the body to the active base. Feeding
interferes quite markedly with oral absorption. Like all
t Moderate susceptibility (MIC 1–4 μg/ml) occurs
in  enterococci, Arcanobacterium pyogenes, some

Chapter 13. Macrolides, Azalides, and Ketolides 215

Table 13.1. In vitro activity (MIC90) of veterinary macrolides (μg/ml) against selected bacterial and mycoplasmal
pathogens.

Organisms Erythromycin Tylosin Spiramycin Tilmicosin Gamithromycin Tulathromycin Tildipirosin

Gram-positive aerobes 2 2 4 0.05* 1 8
Arcanobacterium pyogenes 0.13 < 0.13 0.25 < 0.13 0.125 > 64
Erysipelothrix rhusiopathiae ≤ 0.25 64 128 32
Rhodococcus equi 0.25 2 8 1
Staphylococcus aureus ≤1 1 4
Streptococcus agalactiae ≤ 0.5 1 0.5*
Streptococus uberis ≤ 0.25
S. equi subsp. zooepidemicus
8 32 32 2 32 8
Gram-negative aerobes 44
Actinobacillus pleuropneumoniae 2 8 128 8 0.5 21
Histophilus somni 1 11
Mannheimia haemolytica 16 128 4 1 84
Pasteurella multocida 21
Bordetella bronchiseptica 16 128 16 0.5
Haemophilus parasuis 4
Moraxella bovis 16
Moraxella bovoculi
2* 8*
Anaerobes
Dichelobacter nodosus 1 16 4
Bacteroides fragilis
Fusobacterium necrophorum 16 ≤ 4
Brachyspira hyodysenteriae
Clostridium perfringens 0.25 1 1 4 64
32 0.25* > 64 > 64
Mycoplasma 8 4 64 4
Mycoplasma bovis > 128 > 128 > 128
Mycoplasma hyorhinis 4 2
Mycoplasma hyopneumoniae
Mycoplasma mycoides subsp. 0.5 0.5 4 > 128 4 1
mycoides 4 > 32
Ureaplasma spp. 128 1 0.5 0.5 > 32
0.06
Leptospira spp. 4 11
Lawsonia intracellularis
0.06 0.06 0.5
*Some reports show resistance.
0.13 0.5 2
0.06 0.06
0.5 64

macrolides, erythromycin is well distributed in the body, Toxicity and Adverse Effects
being concentrated in tissues, although penetration into The incidence of serious adverse effects is relatively
cerebrospinal fluid is low. Prostatic fluid concentrations low and depends upon the animal species. One prob-
are approximately half that of serum concentration. The lem shared with all macrolides is their irritating
drug is metabolized and excreted largely in the bile and, nature, which leads to severe pain on IM injection,
although some intestinal reabsorption occurs, most is thrombophlebitis and periphlebitis after IV injection,
lost in feces. Urinary excretion is only 3–5% of the total and an inflammatory reaction after intramammary
administered dose. administration. Dose-related gastrointestinal distur-
bances (nausea, vomiting, diarrhea, intestinal pain)
Erythromycin is available for parenteral injection as occur in most animals species treated with erythro-
the base, glucoheptonate, or lactobionate. Parenteral mycin, either as a result of disruption of the normal
administration causes tissue irritation at the site of intestinal microflora, or as a result of stimulatory
administration.

216 Section II. Classes of Antimicrobial Agents

effects on smooth muscle because erythromycin ing calves. Because of this effect combined with poor
binds motilin receptors. These adverse effects are not absorption, oral administration of erythromycin to
life threatening except in adult horses, where mac- cattle is not recommended. The drug appears safe in
rolides, because they are largely excreted in the bile, dogs and cats. The estolate form has been associated
can lead to serious diarrheic illness. Deaths have with self-limiting cholestatic hepatitis and jaundice
occurred due to Clostridium difficile in adult horses with abdominal pain, especially with repeated and
administered erythromycin (Gustafsson et al., 1997). prolonged use or in patients with preexisting hepatic
Interestingly, severe C. difficile diarrheal illness has disease.
also developed in the mares of foals treated orally
with erythromycin and rifampin for Rhodococcus equi Other adverse effects of erythromycin in foals include
infection. This may be a direct effect of mares ingest- hyperthermia and respiratory distress that may be more
ing small quantities of antibiotic from the feces of marked in foals kept in high environmental tempera-
their foals or an indirect effect of mares acquiring tures (Traub-Dargatz et al., 1996).
erythromycin-resistant C. difficile infection from
their foals, or a combination of these circumstances Administration and Dosage
(Båverud et al., 1998). Deaths from typhlocolitis have Dosages of erythromycin are shown in Table 13.2. When
also been reported in rabbits. Oral administration of administered IV, erythromycin must be diluted and
erythromycin has caused severe diarrhea in ruminat- administered by slow infusion to prevent adverse
reactions.

Table 13.2. Usual dosages of selected macrolides in animals.

Species Drug Dosage (mg/kg) Route Interval (h)

Dog/cat Erythromycin 10–20 PO 8–12
Ruminants Clarithromycin 5–10 PO 12
Azithromycin 5 (cat), 10 (dog) PO 24
Horsesb Tylosin 10–20 PO 12
Swine 5–10 IM 12
Erythromycin
Tylosin 1.1–2.2 IM 24
Tilmicosina 4–10 IM 24
Tulathromycin 10 SC Single dose
Gamithromycin 2.5 SC Single dose
Tildipirosin 6 SC Single dose
4 SC Single dose
Erythromycin
Erythromycin 25 PO 6–8
Clarithromycin 5 IV* 6
Azithromycin 7.5 PO 12
10 PO, IV* 24–48
Erythromycin
Tylosin 2–20 IM 12–24
Tilmicosin 9 IM 12–24
Tulathromycin 200–400 g/ton of feed
Tildipirosin 2.5 IM Single dose
Tylvalosin 4 IM Single dose
Tylvalosin 50–100 g/ton of feed
50 ppm Water

*Slow iv infusion.
aCattle and sheep only.
bMainly indicated in foals.

Chapter 13. Macrolides, Azalides, and Ketolides 217

Clinical Applications Dogs and Cats. Erythromycin may be a second choice
Erythromycin is a drug of choice to prevent or treat for infections caused by Gram-positive cocci and anaer-
Campylobacter jejuni diarrhea or abortion. Erythromycin obic bacteria. It is the drug of choice in treating C. jejuni
is also used as an alternative to penicillin in penicillin- enteritis (Monfort et al., 1990).
allergic animals in the treatment of infections caused by
susceptible Gram-positive aerobes, a less useful alterna- Poultry. Erythromycin is administered in water for
tive to clindamycin or metronidazole in anaerobic infec- the prevention and treatment of staphylococcal or strep-
tions, an alternative to ampicillin or amoxycillin in the tococcal infection, necrotic dermatitis, infectious
treatment of leptospirosis, and an alternative to tetracy- coryza, and M. gallisepticum infection.
clines in rickettsial infections. The generally bacterio-
static nature of the drug is a disadvantage of erythromycin Bibliography
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Alt DP, Bolin CA. 1996. Preliminary evauation of antimicro-
Cattle, Sheep, and Goats. Erythromycin has limited bial agents for treatment of Leptospira interrogans serovar
use in respiratory disease, as H. somni, A. pyogenes, and pomona infection in hamsters and swine. Am J Vet Res
anaerobic bacteria are often moderately susceptible, and 57:59.
some mycoplasma and most Mannheimia haemolytica
isolates are resistant. Due to the extreme pain associated Båverud V, et al. 1998. Clostridium difficile assoicated with
with parenteral injection, it should be avoided when acute colitis in mares when their foals are treated with
other antimicrobial drugs are available. Erythromycin is erythromycin and rifampicin for Rhodococcus equi pneu-
perhaps most useful in its intramammary infusion form monia. Equine Vet J 30:482.
for lactating and dry-cow therapy of mastitis where it
has a short milk withdrawal time (36 hours). A single Gustafsson A, et al. 1997. The association of erythromycin
IM injection of 10 mg/kg was effective in the treatment ethylsuccinate with acute colitis in horses in Sweden.
of virulent footrot in sheep (Ware et al., 1994). Equine Vet J 29:314.

Swine. Erythromycin has little place in the treatment Lavoie JP, et al. 2000. Equine proliferative enteropathy: a
of swine infections with the possible exceptions of lepto- cause of weight loss, colic, diarrhoea and hypoproteinae-
spirosis (Alt and Bolin, 1996). mia in foals on three breeding farms in Canada.Equine Vet
J 32:418.
Horses. Erythromycin is an alternative to penicillin G
or trimethoprim-sulfonamide in the treatment of staph- McOrist S, et al. 1995. Antimicrobial susceptibility of ileal
ylococcal and streptococcal infections. The potential symbiont intracellularis isolated from pigs with prolifera-
for  inducing diarrhea limits its use in adult horses. tive enteropathy. J Clin Microbiol 33:1314.
Erythromycin is a drug of choice in the treatment of
Rhodococcus equi pneumonia in foals, and should be Monfort JD, et al. 1990. Efficacies of erythromycin and
used in combinations with rifampin, both for the syner- chloramphenicol in extinguishing fecal shedding of
gistic effect and to reduce the risk of emergence of resist- Campylobacter jejuni in dogs. J Am Vet Med Assoc
ant mutants. Intramuscular injection causes severe local 196:1069.
irritation in horses. The combination of orally adminis-
tered erythromycin and rifampin has been used success- Palmer JE, Benson CE. 1992. Effect of treatment with eryth-
fully to treat experimentally induced Neorickettsia romycin and rifampin during the acute stages of experi-
risticii infection and may represent an alternative to tet- mentally induced equine ehrlichial colitis in ponies. Am J
racyclines (Palmer and Benson, 1992). Erythromycin, Vet Res 53:2071.
alone or in combination with rifampin, is also the treat-
ment of choice for Lawsonia intracellularis infections in Traub-Dargatz J, et al. 1996. Hyperthermia in foals treated
foals (Lavoie et al., 2000). with erythromycin alone or in combination with rifapin
for respiratory disease during hot environmental condi-
tions. Am Assoc Equine Pract 42:243.

Ware JKW, et al. 1994. Efficacy of erythromycin compared
with penicillin/streptomycin for the treatment of virulent
footrot in sheep. Aust Vet J 71:89.

Tylosin

Tylosin is a macrolide antibiotic isolated from
Streptomyces fradiae. Its chemical structure and its
mechanism of action are similar to other macrolide
antibiotics.

218 Section II. Classes of Antimicrobial Agents

Antimicrobial Activity Mycoplasma tylosin is, like erythromycin, a second-
Tylosin has a similar spectrum of activity to eryth- choice antibiotic in most clinical situations.
romycin. It is less active against bacteria, except for
B. hyodysenteriae, but more active against a broad range Cattle, Sheep, and Goats. Tylosin is used in cattle pri-
of Mycoplasma spp. (Table 13.1). marily to treat pneumonia associated with Mycoplasma
bovis and otitis media and interna in calves. Other pos-
Pharmacokinetic Properties sible indications include treatment of foot rot, metritis,
The pharmacokinetic properties of tylosin are charac- pinkeye, and mastitis caused by Gram-positive cocci.
teristic of the macrolides in general. Tylosin is a weak Tylosin may be administered at low concentrations to
base (pKa 7.1) and is highly lipid soluble. The elimina- feedlot cattle on high-concentrate diets to improve
tion half-life in dogs and cattle is about 1 hour with weight gain and feed efficiency, and to prevent liver
apparent volumes of distribution of 1.7 and 1.1 L/kg, abscesses. Because of the availability of newer macrolide
respectively. The half-life is considerably longer in antibiotics, this is now the major use of tylosin.
sheep, goats and pigs, at approximately 4 hours.
In cattle, tylosin (7.5–15 mg/kg IM twice a day) has
Toxicity and Adverse Effects been successful in controlling and eliminating experi-
Tylosin is a relatively safe drug. Its toxic effects are gen- mental Mycoplasma mycoides pneumonia. In calves the
erally similar to those reported for erythromycin. The drug has been used effectively to treat Mycoplasma bovis
drug is irritating to tissue when administered IM or SC. pneumonia and arthritis. However, in studies where tylo-
Pigs have been reported to react to injection by develop- sin was dosed IM at 10 mg/kg twice a day it delayed, but
ing edema, pruritus, edema of rectal mucosa, and mild did not prevent, experimentally induced M. bovis arthri-
anal protrusion. These effects may in part be attributed tis (Stahlheim, 1976). In goats, tylosin is a drug of choice
to the drug vehicle. Tylosin has been reported to cause for treating Mycoplasma pneumonia, such as that caused
fatal diarrhea in a horse. Inadvertent feeding of dairy by M. mycoides spp. capri. A high dosage of 25–35 mg/kg
cows with a concentrate contaminated with 7–20 ppm IV at 8- to 12-hour intervals is recommended.
of tylosin resulted in ruminal stasis, inappetance, foul-
smelling feces, and decreased milk production. Many of Swine. Tylosin is used in some countries to promote
the cows became hyperesthetic and some became growth and improve weight gain. For the treatment of
recumbent (Crossman and Poyser, 1981). Intravenous atrophic rhinitis, injection of piglets for variable periods
administration in cattle has produced shock, dyspnea, has reduced frequency of the disease, suggesting that
and depression. Tylosin and spiramycin have induced tylosin inhibits Pasteurella multocida (or its production
contact dermatitis in veterinarians. of Pmt toxin), despite the bacteria’s relatively high MIC.
Injection of neonatal pigs has reduced the frequency of
Administration and Dosage M. hyopneumoniae lesions (Kunesh, 1981). Tylosin was
Tylosin is administered by IM injection (Table 13.2), by not as effective as tiamulin in controlling an experimen-
the intramammary route, or for feed incorporation in tal mixed Mycoplasma and bacterial pneumonia
swine. Tylosin tartrate is readily absorbed from the (Hannan et al., 1982). Tylosin, 8.8 mg/kg twice a day IM,
intestine, but tylosin phosphate is relatively poorly or tylosin-sulfonamide, 100 ppm of each drug in feed,
absorbed. was effective in treating pigs with experimentally
induced P. multocida and A. pyogenes pneumonia
Clinical Applications (Matsuoka et al., 1983).
Tylosin is not as active as erythromycin against most
bacteria but has greater activity against Mycoplasma spp. Control of swine dysentery by tlosin is hampered by
In pigs, where it is also used as a growth promoter, the development of resistance; the in vivo effect of the
its use in the prevention and treatment of swine dysen- drug varies with the MIC, which ranges from 4 to > 32
tery and Mycoplasma infections is being replaced by μg/ml. Derivatives of tylosin may have greater activity
the  more active tiamulin. Apart from its use against against resistant organisms (Jacks et al., 1986). Tylosin
(100 ppm) is effective in preventing or treating prolifera-
tive enteropathy (McOrist et al., 1997). Other potential

Chapter 13. Macrolides, Azalides, and Ketolides 219

uses include parenteral treatment of erysipelas and Bibliography
infections involving A. pyogenes and anaerobes. Tylosin
(44 mg/kg IM once daily for 5 days) effectively treated Aarestrup FM, et al. 1998. Surveillance of antimicrobial
experimentally induced leptospirosis in swine (Alt and resistance in bacteria isolated from food animals to anti-
Bolin, 1996). microbial growth promoters and related therapeutic agents
in Denmark. APMIS 106:606.
Horses. Injection of tylosin has been fatal to horses.
There is no experience with its oral administration but Alt DP, Bolin CA. 1996. Preliminary evaluation of antimicro-
no indication for such use, which might be likely to bial agents for treatment of Leptospira interrogans serovar
result in enterocolitis. pomona infection in hamsters and swine. Am J Vet Res 57:59.

Dogs and Cats. Tylosin has been used successfully in Catania S, et al. 2010. Treatment of eggshell abnormalities
dogs to treat abscesses, wound infections, tonsillitis, tra- and reduced egg production caused by Mycoplasma syno-
cheobronchitis, and pneumonia caused by pathogens viae infection. Avian Dis 54:961.
such as staphylococci, streptococci, anaerobes, and
Mycoplasma. Occasional pain and swelling at the injec- Crossman PJ, Poyser MR. 1981. Effect of inadvertently feed-
tion site and vomiting after oral administration have ing tylosin and tylosin and dimetridazole to dairy cows.
been reported. A tylosin-sulfonamide combination is Vet Rec 108:285.
licensed for the treatment of upper respiratory tract
infections in dogs. Tylosin is often effective in the treat- Hannan PCT, et al. 1982. Tylosin tartrate and tiamulin effects
ment of the upper respiratory tract infection complex of on experimental piglet pneumonia induced with pneu-
cats, possibly because of its effect against Chlamydophila monic pig lung homogenate containing mycoplasma,
and Mycoplasma. Tylosin administered orally has been bacteria, and viruses. Res Vet Sci 33:76.
shown to be effective in the treatment of Staphylococcus
intermedius pyoderma in dogs (Scott et al., 1994; Harvey, Harvey RG. 1996. Tylosin in the treatment of canine superfi-
1996); a dose of 10 mg/kg q 12 h was shown to be almost cial pyoderma. Vet Rec 139:185.
as effective as 20 mg/kg q 12 h (Scott et al., 1996). Therapy
with oral tylosin has been successful for the attenuation Jacks TM, et al. 1986. 3-acetyl-4Ν-isovaleryl tylosin for pre-
of diarrhea in dogs with chronic enteropathies for which vention of swine dysentery. Am J Vet Res 47:2325.
specific causes have been ruled out (Westermark et al.,
2005). In a recent randomized double-blinded prospec- Johnston WS. 1975. Eradication of Str. agalactiae from
tive clinical trial, tylosin at 25 mg/kg q 24 h resulted in infected herds using erythromycin. Vet Rec 96:430.
normal fecal consistency in 17 of 20 (85%) dogs whereas
administration of a placebo improved fecal consistency Jordan FTW, et al. 1993. A comparison of the efficacy of dano-
in only 2 of 7 dogs (Kilpinen et al., 2011) floxacin and tylosin in the control of Mycoplasma gallisepti-
cum infection in broiler chickens. J Vet Pharm Ther 16:79.
Poultry. Tylosin has been used by IM injection for the
control of Mycoplasma infections and added to the water Kilpinen S, et al. 2011. Effect of tylosin on dogs with sus-
o control of avian spirochetosis. Resistance in some pected tylosin-responsive diarrhea: a placebo-controlled,
M. gallisepticum isolates may reduce the efficacy of tylo- randomized, double-blinded, prospective clinical trial.
sin (Migaki et al., 1993). In one study, tylosin was found Acta Vet Scand 53:26.
to be almost as effective as danofloxacin in control of
infection caused by Mycoplasma gallisepticum in broiler Kunesh JP. 1981. A comparison of two antibiotics in treating
chickens (Jordan et al., 1993). Administration of tylosin Mycoplasma pneumonia in swine. Vet Med Small Anim
in drinking water for 5 days resulted in an immediate Clin 76:871.
resolution of eggshell abnormalities associated with
Mycoplasma synoviae infection (Catania et al., 2010). Matsuoka T, et al. 1983. Therapeutic effect of injectable tylo-
sin against induced pneumonia in pigs. Vet Med Small
Anim Clin 78:951.

McOrist S, et al. 1997. Oral administration of tylosin phos-
phate for treatment and prevention of proliferative enter-
opathy in pigs. Am J Vet Res 58:136.

Migaki TT, et al. 1993. Efficacy of danofloxacin and tylosin
in  the control of mycoplsmosis in chicks infected with
tylosin-susceptible or tylosin-resistant field isolates of
Mycoplasma gallisepticum. Avian Dis 37:508.

Scott DW, et al. 1994. Efficacy of tylosin tablets for the treat-
ment of pyoderma due to Staphylococcus intermedius
infection in dogs. Can Vet J 35:617.

Scott DW, et al. 1996. Further studies on the efficacy of tylosin
tablets for the treatment of pyoderma due to Staphylococcus
intermedius infection in dogs. Can Vet J 37:617.

Stahlheim OHV. 1976. Failure of antibiotic therapy in calves
with mycoplasmal arthritis and pneumonia. J Am Vet Med
Assoc 189:1096.

Westermark E, et al. 2005. Tylosin-responsive chronic diar-
rhea in dogs. J Vet Intern Med. 19:177.

220 Section II. Classes of Antimicrobial Agents

Spiramycin last milking gave effective milk drug concentrations
for  6–8 days (Ziv, 1974). In lactating cows, a single
Spiramycin is several times less active against bacteria intramammary dose of 600 mg resulted in effective con-
than erythromycin. Its spectrum of activity is similar to centrations for 36–48 hours, but persistent residues limit
that of the other macrolides, but it is not as effective the use of the drug. Parenteral administration of
against Mycoplasma as tylosin or tiamulin. Resistance, spiramycin for 3–5 days did not give satisfactory results
antimicrobial drug interactions, and toxic properties are in mastitis caused by penicillin-resistant S. aureus
similar to those of the other macrolides. (Pyorala and Pyorala, 1998). Spiramycin administered
orally at a dose of 100 mg/kg in the last third of gestation
Despite relatively poor activity in vitro, spiramycin to ewes effectively prevented experimental Toxoplasma
has quite exceptional ability to concentrate in tissues, abortion. Bioavailability after oral administration is
in part by tissue binding. This results in concentrations in limited in ruminants. Spiramycin, administered at
organs reaching 25–60 times those of serum. The drug 20–30 mg/kg IM, successfully treated ovine infectious
persists even when serum concentrations are negligible. rickettsial keratoconjunctivitis; in serious cases the drug
Thus, spiramycin has the paradoxical effect of being less should be repeated 5 and 10 days after the first injection
active than erythromycin in vitro but as or more active (Konig, 1983). One interesting potential application is
in vivo. Like other macrolides, it also has a direct effect the use of a single injection of the parenteral dosage
on phagocytic cells and as such, has particular potential form of spiramycin to treat endometritis in sheep and
against intracellular organisms. In humans, it is used in cattle, because of the extraordinarily long half-life of the
the treatment of toxoplasmosis (Hotop et al., 2012). In drug (Cester et al., 1990).
calves, Schilferli et al. (1981) found that a parenteral
administration of 50 mg/kg twice a day for 5 days Swine and Poultry
resulted in lung concentrations of approximately 100 Spiramycin has the same applications as tylosin in pigs
μg/g. Not all this drug is active; in mammary tissue and poultry.
about 75% is inactive. One result of its tissue concentra-
tion is the persistence of drug residues for prolonged Bibliography
periods, a particular problem in the treatment of masti-
tis in lactating cows but also more generally in food ani- Aarestrup FM, et al. 1998. Surveillance of antimicrobial
mals. Spiramycin is used extensively in France for the resistance in bacteria isolated from food animals to anti-
treatment of infections in farm animals. It has the same microbial growth promoters and related therapeutic agents
applications as tylosin. in enmark. APMIS 106:606.

Spiramycin was used extensively in Europe as a broiler Cester CC, et al. 1990. Spiramycin concentrations in plasma
chicken growth promoter prior to the ban on these and genital-tract secretions after intravenous injection in
products by the European Union. Resistance in bacteria the ewe. J Vet Pharm Ther 13:7.
isolated from chickens fed spiramycin is widespread in
Europe (Aarestrup et al., 1998). Hotop A, et al. 2012. Efficacy of rapid treatment initiation
following primary Toxoplasma gondii infection during
Cattle, Sheep, and Goats pregnancy. Clin Infect Dis 54:1545.
Spiramycin has similar applications to tylosin. The drug
has been used successfully to treat contagious bovine Konig CDW. 1983. “Pink eye” or “zere oogjes” or keratocon-
pleuropneumoniae when administered at 25 mg/kg IM junctivitis infectiosa ovis (KIO). Clinical efficacy of a
at 48-hour intervals for 3 doses (Provost, 1974). In one number of antimicrobial therapies. Vet Q 5:122.
field trial of the treatment of bovine respiratory disease,
spiramycin was considerably less effective than florfeni- Madelenat A, et al. 1997. Efficacite comparee du florfenicol et
col (Madelenat et al., 1997). In another study, a dose of de la spiramycine longue action, associe a la flunixine
20 mg/kg resulted in spiramycin concentrations in mas- meglumine, dans le traitement des maladies respiratoires
titic milk of greater than 2.5 μg/ml for 48 hours after IM du veau de boucherie. Rec Med Vet 173:113.
injection. Intramuscular injection of this dose after the
Provost A. 1974. Essai de traitement de la spiramycin chez les
brebis et les vaches laitieres. Can Med Vet 43:140.

Pyorala SH, Pyorala EO. 1998. Efficacy of parenteral admin-
istration of three antimicrobial agents in treatment of clin-
ical mastitis in lactating cows: 487 cases (1989–1995).
J Am Vet Med Assoc 212:407.

Chapter 13. Macrolides, Azalides, and Ketolides 221

Renard L, et al. 1996. Pharmacokinteic-pharmacodynamic after oral administration to pigs (Shen et al., 2005). In
model for spiramycin in staphylococcal mastitis. J Vet contrast, tilmicosin is not absorbed after oral adminis-
Pharm Ther 19:95. tration to horses. After IM or SC administration to
horses, tilmicosin accumulates in phagocytic cells and
Schilferli D, et al. 1981. Distribution tissulaire de la penicil- lung tissue (Womble et al., 2006; Clark et al., 2008).
lin, de l’oxytetracycline et del a spiramycine chez le veau au
cours d’une antibiotique courante. Schweiz Arch Tierheilkd Toxicity and Adverse Effects
123:507. Tilmicosin is potentially toxic to the cardiovascular sys-
tem, which varies to some extent with species. The drug
Ziv G. 1974. Profil pharmacocinetique de la spiramycine is fatal to swine when administered by IM injection at
chez les brebis et les vaches laitieres. Cah Med Vet 43:371. doses ranging between 10 and 20 mg/kg. Care should be
taken to avoid accidental injection of people, which can
Tilmicosin be fatal. The toxic dose for goats is only about 30 mg/kg
SC, or ≥ 2.5 mg/kg IV. In horses, SC or IM administra-
Tilmicosin, 20-deoxo-20-(3,5-dimethylpiperidin-1-yl) tion of tilmicosin has resulted in severe reactions at the
desmycosin, is a semisynthetic derivative of tylosin. injection site and in development of diarrhea in some
horses (Womble et al., 2006; Clark et al., 2008). The
Antimicrobial Activity toxic effects of tilmicosin are mediated through its
Tilmicosin has antibacterial and antimycoplasma activ- effects on the heart, possibly via rapid depletion of cal-
ity between that of erythromycin and tylosin (Table 13.1). cium (Main et al., 1996).
Typical of macrolides, it inhibits Gram-positive bacteria
including Clostridium spp., Staphylococcus spp., and Administration and Dosage
Streptococcus spp., Gram-negative bacteria including Administration is summarized in Table 13.2.
Actinobacillus spp., Campylobacter spp., Histophilus
spp., and Pasteurella spp. All Enterobacteriaceae are Clinical Applications
resistant. Mycoplasma susceptibility can be quite varia- Cattle, Sheep, and Goats. Tilmicosin has been devel-
ble. Mannheimia haemolytica isolates from cattle with oped as a long-acting formulation for use in bovine res-
respiratory disease are regarded as susceptible if their piratory disease. A single SC dose of 10 mg/kg results in
MIC is ≤ 8 μg/ml, intermediate if MIC is 16 μg/ml, and lung concentrations exceeding the MIC of M. haemo-
resistant if their MIC is ≥ 32 μg/ml. Tilmicosin resistance lytica for 72 hours. Experimental and field data support
among M. haemolytica (6 of 745 isolates or 0.8%) and the value of single-dose SC tilmicosin prophylaxis on
P. multocida (16 of 231 isolates or 6.9%) isolates is arrival of cattle in feedlots and in the treatment in pneu-
uncommon (McClary et al., 2011). Pasteurella multocida monia of cattle (Ose and Tonkinson, 1988; Schumann
and Actinobacillus pleuropneumoniae isolates from et al., 1991; Young, 1995; Musser et al., 1996; Rowan
swine with respiratory disease are regarded as susceptible et al., 2004). Doses of 20 mg/kg appeared slightly more
if their MIC is ≤ 16 μg/ml and resistant if their MIC is ≥ effective than 10 mg/kg (Gorham et al., 1990). Repeat
32 μg/ml. injections after 3 days are necessary in some animals
(Laven and Andrews, 1991; Scott, 1994). Tilmicosin is
Pharmacokinetic Properties not approved for use in lactating cattle because of the pro-
The pharmacokinetic properties of tilmicosin are simi- longed period (2–3 weeks) during which milk residues
lar to that of macrolides in general, and are character- can be detected. Intramammary tilmicosin at drying-off
ized by low serum concentrations but large volumes of has been shown to be efficacious in curing some existing
distribution (> 10 L/kg), with accumulation and persis- S. aureus infection (Dingwell et al., 2003). However, tilm-
tence in tissues including the lung, which may concen- icosin should not be administered by the intramammary
trate the drug 20-fold compared to serum. Subcutaneous route in lactating dairy cows because of the persistence
tilmicosin is 100% bioavailable in cattle and has a half- of  residues. Milk from all glands of any lactating
life ranging between 21 and 35 hours (Lombardi et al.,
2011). Cows administered 10 mg/kg SC as a single dose
maintained milk concentrations > 0.8 μg/ml for 8–9 days
(Ziv et al., 1995). Tilmicosin is rapidly absorbed and
slowly eliminated (elimination half-life of 25 hours)

222 Section II. Classes of Antimicrobial Agents

cows accidentally treated should be discarded for a min- Bibliography
imum of 82 days following intramammary administra-
tion (Smith et al., 2009). Charleston B, et al. 1998. Assessment of the efficacy of tilmi-
cosin as a treatment for Mycoplasma gallisepticum infec-
Tilmicosin is approved for single-dose SC treat- tions in chickens. Avian Pathol 27:190.
ment  of ovine respiratory disease associated with
M.  haemolytica. Administration of tilmicosin may be Clark C, et al. 2008. Pharmacokinetics of tilmicosin in equine
fatal in goats. tissues and plasma. J Vet Pharmacol Therap 31:66.

Swine. Tilmicosin has been shown by experimental Dingwell RT, et al. 2003. Efficacy of intramammary tilmico-
and clinical studies to be useful as an oral medication in sin and risk factors for cure of Staphylococcus aureus
swine (200–400 ppm) in the control of Actinobacillus infection in the dry period. J Dairy Sci 86:159.
spp. or P. multocida pneumonia (Paradis, 2004). It may
also be useful in the control of atrophic rhinitis. In feed, Fittipaldi N, et al. 2005. Assessment of the efficacy of tilmico-
treatment with 400 ppm of tilmicosin phosphate signifi- sin phosphate to eliminate Actinobacillus pleuropneumo-
cantly reduced the presence of A. pleuropneumoniae on niae from carrier pigs. Can J Vet Res 69:146.
the surface of tonsils but was unable to completely elimi-
nate the organism from deeper tonsillar tissues nor to Gorham PE, et al. 1990. Tilmicosin as a single injection treat-
prevent bacterial shedding by carrier animals (Fittipaldi ment for respiratory disease of feedlot cattle. Can Vet J
et al., 2005). There is no information on its effect against 31:826.
Mycoplasma pneumonia. Tilmicosis is effective in vitro
against Lawsonia intracellularis and would likely control Laven R, Andrews AH. 1991. Long-acting antibiotic formu-
proliferative enteropathy. Tilmicosin should only be lations in the treatment of calf pneumonia: A comparative
administered orally to swine as IM administration study of tilmicosin and oxytetracycline. Vet Rec 129:109.
causes vomiting, tachypnea, convulsions, and some-
times death. Lombardi KR, et al. 2011. Pharmacokinetics of tilmicosin
in  beef cattle following intravenous and subcutaneous
Rabbits. Tilmicosin at 25 mg/kg SC was effective in administration. J Vet Pharmacol Therap 34:583.
treating pasteurellosis in rabbits; this dose may need to
be repeated after 3 days to further enhance a clinical Main BW, et al. 1996. Cardiovascular effects of the macrolide
cure (McKay et al., 1996). antibiotic, tilmicosin, administered alone or in combina-
tion with propanolol or dobutamine, in conscious unre-
Poultry. Tilmicosin is effective in the treatment of strained dogs. J Vet Pharm Ther 19:225.
experimentally induced Mycoplasma gallisepticum
infection when administered at 50 mg/l of drinking McClary DG, et al. 2011. Relationship of in vitro minimum
water for 3 or 5 days (Charleston et al., 1998). At 300– inhibitory concentrations of tilmicosin against
500 g/ton it prevented infection; interestingly, use of the Mannheimia haemolytica and Pasteurella multocida and in
pellet binder bentonite inhibited the effect of tilmicosin vivo tilmicosin treatment outcome among calves with
in a concentration-dependent manner (Shryock et al., signs of bovine respiratory disease. Am J Vet Res 239:129.
1994).
McKay SG, et al. 1996. Use of tilmicosin for treatment of
Horses. Because of severe injection site reactions and pasteurellosis in rabbits. Am J Vet Res 57:1180.
the risk of colitis, tilmicosin is rarely if ever indicated for
use in horses. Musser J, et al. 1996. Comparison of tilmicosin with long-
acting oxytetracycline for treatment of repsiratory disease
Other Species. Tilmicosin is not approved or recom- in calves. J Am Vet Med Assoc 208:102.
mended for use in species other than those described
above because of toxicity. Ose EE, Tonkinson LV. 1988. Single-dose treatment of neo-
natal calf pneumonia with the new macrolide antibiotic
tilmicosin. Vet Rec 123:367.

Paradis MA. 2004. Efficacy of tilmicosin in the control of
experimentally induced Actinobacillus pleuropneumoniae
infection in swine. Can J Vet Res 68:7.

Rowan TG, et al. 2004. Efficacy of danofloxacin in the treat-
ment of respiratory disease in European cattle. Vet Rec
154:585.

Schumann FJ, et al. 1991. Prophylactic medication of feedlot
calves with tilmicosin. Vet Rec 128:278.

Scorneaux B, Shryock TR. 1998. Intracellular accumulation,
subcellular distribution and efflux of tilmicosin in swine
phagocytes. J Vet Pharm Ther 21:257.

Scott PR. 1994. Field study of undifferentiated respiratory
disease in housed beef calves. Vet Rec 134:325.

Shen J, et al. 2005. Pharmacokinetics of tilmicosin after oral
administration in swine. Am J Vet Res 66:1071.

Shryock TR, et al. 1994. Effect of bentonite incorporated in a
feed ration with tilmicosin in the prevention of induced

Chapter 13. Macrolides, Azalides, and Ketolides 223

Mycoplasma gallisepticum airsacculitis in broiler chickens. bioavailability of tulathromycin following SC (cattle)
Avian Dis 38:501. and IM (swine) administration is approximately 90%
Smith GW, et al. 2009. Elimination kinetics of tilmicosin fol- and the elimination half-life is about 90 h. The apparent
lowing intramammary administration in lactating dairy volume of distribution following IV administration
cattle. J Am Vet Assoc 234:245. to  cattle is 12 L/kg. Peak lung concentrations are
Womble A, et al. 2006. Pulmonary disposition of tilmicosin approximately 4 μg/g. Lung concentrations are 25–180
in foals and in vitro activity against Rhodococcus equi and times higher than concurrent serum concentrations.
other common equine bacterial pathogens. J Vet Pharm Elimination half-life from lung tissue of cattle is approx-
Ther 29:561. imately 11 days (Nowakoski et al., 2004; Benchaoui
Young C. 1995. Antimicrobial metaphylaxis for undifferenti- et al., 2004; Cox et al., 2010). Tulathromycin concentrates
ated bovine respiratory disease. Comp Cont Ed Pract Vet in bronchoalveolar cells of cattle and horses and is elimi-
17:133. nated slowly from these cells (Scheuch et al., 2007; Cox
Ziv G, et al. 1995. Tilmicosin antibacterial activity and phar- et al., 2010). Oral bioavailability in pigs is approximately
macokinetics in cows. J Vet Pharm Ther 18:340. 50% (Wang et al., 2011).

Tulathromycin Toxicity and Adverse Effects
Tulathromycin is safe to use in swine and cattle. No seri-
Tulathromycin, a semisynthetic macrolide, consists of ous adverse events were noted during the clinical devel-
an equilibrated regioisomeric mixture of a 13-membered opment program of the drug. At 10 times the
ring (10%) and a 15-membered ring (90%) macrolide. recommended dosage, the most significant adverse
The unique structural feature of this antimicrobial effects were associated with pain, swelling and discol-
places it in a novel category of macrolides termed oration at the injection site. Based on limited data, the
triamilides. drug appears to be safe in goats (Clothier et al., 2010)
and foals (Venner et al., 2007). Safety has not been
Antimicrobial Activity assessed in other species.
The antimicrobial activity of tulathromycin appears
similar to that of tilmicosin. The drug is active in vitro Administration and Dosage
against many Gram-negative pathogens including Administration is summarized in Table 13.2.
M. haemolytica, P. multocida, H. somni, Moraxella bovis,
Fusobacterium necrophorum, A. pleuropneumoniae, Clinical Applications
Haemophilus parasuis (MIC90 2 μg/ml), and Bordetella Cattle. Tulathromycin is approved for the treatment
bronchiseptica (MIC90 8 μg/ml). Tulathromycin is active or control of bovine respiratory disease caused by
in vitro against most Mycoplasma spp. although resist- M. haemolytica, P. multocida, H. somni, and Mycoplasma
ance is not uncommon. The activity of tulathromycin bovis. Additional approved indications include the treat-
against Gram-positive bacterial pathogens has not yet ment of infectious bovine keratoconjunctivitis associated
been studied extensively. Based on a small number of with Moraxella bovis, and bovine foot rot (interdigital
isolates, tulathromycin is active against Arcanobacterium necrobacillosis) associated with Fusobacterium necro-
pyogenes (MIC90 1 μg/mL) but poorly active against phorum and Porphyromonas levii. In multiple studies,
Rhodococcus equi (MIC90 > 64 μg/mL; Table  13.1). tulathromycin was more effective than florfenicol or
Mannheimia haemolytica, Pasteurella multocida and tilmicosin in the prevention or treatment of undifferen-
Histophilus somni isolates from cattle with respiratory tiated respiratory disease in cattle (Nutsch et al., 2005a;
disease are regarded as susceptible if their MIC is ≤ 16 μg/ Rooney et al., 2005; Skogerboe et al., 2005). Tulath-
ml and resistant if their MIC is ≥ 64 μg/ml. romycin was also effective in the treatment of calves
experimentally infected with M. bovis (Godinho
Pharmacokinetic Properties et  al.,  2005). Interestingly, the drug was as effective
The pharmacokinetics of tulathromycin in cattle, swine, regardless of the MIC of the challenge strain
goats, and horses are characterized by rapid absorption (1  or > 64 μg/  ml). Although this is not an approved
from the injection site, extensive distribution into
tissues, and slow elimination that collectively contri-
bute  to high and sustained lung concentrations. The

224 Section II. Classes of Antimicrobial Agents

indication, tulathromycin has been shown to clear Bibliography
Leptospira borgpetersenii serovar hardjo type hardjo-
bovis from the urine and kidneys of experimentally Benchaoui HA, et al. 2004. Pharmacokinetics and lung tissue
infected cattle (Cortese et al., 2007). concentrations of tulathromycin in swine. J Vet Pharmacol
Ther 27:203.
Swine. Tulathromycin is indicated for the treatment of
swine respiratory disease caused by A. pleuropneumoniae, Carlson K, et al. 2010. Antimicrobial activity of tulathromy-
P. multocida, B. bronchiseptica, H. parasuis, or cin and 14 other antimicrobials against virulent
Mycoplasma hyopneumoniae. The drug is also approved Rhodococcus equi in vitro. Vet Ther 11:E1.
for the control of A. pleuropneumoniae, P. multocida, or
Mycoplasma hyopneumoniae in groups of pigs where Cortese VS, et al. 2007. Evaluation of two antimicrobial ther-
swine respiratory disease has been diagnosed. apies in the treatment of Leptospira borgpetersenii serovar
Tulathromycin was as at least as effective as ceftiofur, hardjo infection in experimentally infected cattle. Vet Ther
florfenicol or tiamulin for the treatment of undifferenti- 8:201.
ated respiratory disease in swine (McKelvie et al., 2005;
Nutsch et al., 2005b). A single dose of tulathromycin Cox SR, et al. 2010. Rapid and prolonged distribution of
was as effective as three daily administrations of enro- tulathromycin into lung homogenate and pulmonary epi-
floxacin for the treatment of pigs inoculated experimen- thelial lining fluid of Holstein calves following a single
tally with M. hyopneumoniae (Nanjiani et al., 2005). subcutaneous administration of 2.5 mg/kg body weight.
Intern J Appl Res Vet Med 8:129.
Sheep and Goats. Although not labeled for use in
small ruminants, tulathromycin would be a reasonable Godinho KS, et al. 2005. Efficacy of tulathromycin in the
alternative for the treatment of respiratory disease in treatment of bovine respiratory disease associated with
small ruminants. In an uncontrolled study of sheep and induced Mycoplasma bovis infections in young dairy
goats with caseous lymphadenitis, closed system lavage calves. Vet Ther 6:96.
in combination with either intralesional or SC adminis-
tration of tulathromycin resulted in resolution of the McKelvie J, et al. 2005. Evaluation of tulathromycin for the
abscesses in the majority of cases (Washburn et al., treatment of pneumonia following experimental infection
2009). However, the in vitro activity of tulathromycin of swine with Mycoplasma hyopneumoniae. Vet Ther 6:197.
against Corynebacterium pseudotuberculosis has not
been studied. Nanjiani IA, et al. 2005. Evaluation of the therapeutic activity
of tulathromycin against swine respiratory disease on
Horses. Tulathromycin was compared to azithromy- farms in Europe. Vet Ther 6:203.
cin-rifampin for the treatment of foals with subclinical
pneumonia as identified by ultrasonographic screening Nowakoski MA, et al. 2004. Pharmacokinetics and lung
on a farm with a high cumulative incidence of R. equi tissue concentrations of tulathromycin, a new triamilide
infections. Although differences in survival were not antibiotic, in cattle. Vet Ther 5:60.
statistically significant, pulmonary abscesses 1 week
after initiation of treatment with tulathromycin were Nutsch RG, et al. 2005a. Comparative efficacy of tulathromy-
significantly larger and duration of therapy was signifi- cin, tilmicosin, and florfenicol in the treatment of bovine
cantly longer, indicating that tulathromycin is not as respiratory disease in stocker cattle. Vet Ther 6:167.
effective as standard therapy with azithromycin-
rifampin (Venner et al., 2007). These results might be Nutsch RG, et al. 2005b. Efficacy of tulathromycin injectable
explained by the fact that tulathromycin is poorly active solution for the treatment of naturally occurring Swine
against R. equi in vitro with an MIC90 > 64 μg/mL respiratory disease. Vet Ther 6:214.
(Carlson et al., 2010).
Rooney KA, et al. 2005. Efficacy of tulathromycin compared
with tilmicosin and florfenicol for the control of respira-
tory disease in cattle at high risk of developing bovine
respiratory disease. Vet Ther 6:154.

Scheuch E, et al. 2007. Quantitative determination of the mac-
rolide antibiotic tulathromycin in plasma and broncho-
alveolar cells of foals using tandem mass spectrometry.
J Chromatogr B Analyt Technol Biomed Life Sci 850:464.

Skogerboe TL, et al. 2005. Comparative efficacy of tulathromy-
cin versus florfenicol and tilmicosin against undifferentiated
bovine respiratory disease in feedlot cattle. Vet Ther 6:180.

Venner M, et al. 2007. Evaluation of tulathromycin in the
treatment of pulmonary abscesses in foals. Vet J 174:418.

Wang X, et al. 2011. Pharmacokinetics of tulathromycin and
its metabolite in swine administered with an intravenous
bolus injection and a single gavage. J Vet Pharmacol Ther
doi: 10.1111/j.1365-2885.2011.01322.x.

Washburn KE, et al. 2009. Comparison of three treatment
regimens for sheep and goats with caseous lymphadenitis.
J Am Vet Med Assoc 234:1162.

Chapter 13. Macrolides, Azalides, and Ketolides 225

Gamithromycin Clinical Applications
Cattle. Gamithromycin is approved for the treatment
Gamithromycin is a semisynthetic azalide approved for or control of bovine respiratory disease associated with
the treatment and control of bovine respiratory disease. M. haemolytica, P. multocida, Mycoplasma bovis, or
Gamithromycin differs from most other macrolides H. somni in beef and non-lactating dairy cattle. The effi-
approved for veterinary use in its structural composi- cacy of gamithromycin for the treatment and control
tion by having a 15-membered semisynthetic lactone of  bovine respiratory disease has been documented
ring with a uniquely positioned alkylated nitrogen atom in  multiple studies (Baggott et al., 2011; Lechtenberg
at the 7a-position. et al., 2011).

Antimicrobial Activity Sheep and Goats. Although not licensed for use in
The antimicrobial activity of gamithromycin appears small ruminants, gamithromycin would be a reasonable
similar to that of other azalides such as azithromycin. alternative for the treatment of respiratory disease in
The drug is active in vitro against M. haemolytica, sheep and goats. Subcutaneous injection of gamithro-
P. multocida, H. somni, Mycoplasma bovis, Streptococcus mycin at a dose of 6 mg/kg was apparently effective in
equi subspecies zooepidemicus and Rhodococcus equi the treatment of footrot-like lesions associated with
(Table  13.1). The activity of gamithromycin against Bacteroides melaninogenicus in a herd of ewes (Sargison
other bacterial pathogens has not been studied. et al., 2011).

Pharmacokinetic Properties Horses. Intramuscular administration of gamithro-
The pharmacokinetics of gamithromycin in cattle are mycin to foals at a dosage of 6mg/kg maintains pulmonary
characterized by rapid absorption from the injection epithelial lining fluid concentrations above the MIC90 for
site, extensive distribution into tissues, and slow elimi- S.  equi subspecies zooepidemicus and phagocytic cell
nation, which collectively contribute to high and sus- concentrations above the MIC90 for R. equi for approxi-
tained concentrations in pulmonary epithelial lining mately 7 days (Berghaus et al., 2012). However, treatment
fluid, bronchoalveolar cells, and lung tissue (Giguère of foals with gamithromycin is not recommended until
et al., 2011). The bioavailability of gamithromycin after the clinical efficacy and the safety of the drug have been
SC administration to cattle is nearly 100% (Huang et al. established.
2010). The apparent volume of distribution after IV
administration is 25 L/kg (Huang et al., 2010). Peak lung Bibliography
concentrations are approximately 28 μg/g after adminis-
tration of an SC dose of 6 mg/kg. Lung concentrations Baggott D, et al. 2011. Demonstration of the metaphylactic
are 16–650 times higher than concurrent plasma con- use of gamithromycin against bacterial pathogens associ-
centrations. Lung elimination half-life values for cattle ated with bovine respiratory disease in a multicentre farm
are 6–7 days (Huang et al., 2010; Giguère et al., 2011). trial. Vet Rec 168:241.

Toxicity and Adverse Effects Berghaus LJ, et al. 2012. Plasma pharmacokinetics, pulmo-
Gamithromycin is safe to use in cattle. No serious nary distribution, and in vitro activity of gamithromycin
adverse events were noted during the clinical develop- in foals. Vet Pharmacol Ther 35:59.
ment program of the drug. Transient discomfort and
mild to moderate injection site swelling may be seen in Giguère S, et al. 2011. Disposition of gamithromycin in
some treated animals. Safety has not been assessed in plasma, pulmonary epithelial lining fluid, bronchoalveolar
other species. cells, and lung tissue in cattle. Am J Vet Res 72:326.

Administration and Dosage Huang RA, et al. 2010. Pharmacokinetics of gamithromycin
Administration and dosages are summarized in in cattle with comparison of plasma and lung tissue con-
Table 13.2. centrations and plasma antibacterial activity. J Vet
Pharmacol Ther 33:227.

Lechtenberg K, et al. 2011. Field efficacy study of gamithro-
mycin for the treatment of bovine respiratory disease asso-
ciated with Mycoplasma bovis in beef and non-lactating
dairy cattle. Intern J Appl Res Vet Med 9:225.

226 Section II. Classes of Antimicrobial Agents

Sargison ND, Scott PR. 2011. Metaphylactic gamithromycin Clinical Applications
treatment for the management of lameness in ewes puta- Cattle. Tildipirosin is approved for the treatment or
tively caused by Bacteroides melaninogenicus. Vet Rec control of bovine respiratory disease associated with
169:556. M.  haemolytica, P. multocida, or H. somni in beef and
non-lactating dairy cattle.
Tildipirosin
Swine. In some countries, tildipirosin is approved for
Tildipirosin is a semisynthetic 16-membered macrolide the treatment of respiratory disease associated with
derived from the naturally occurring tylosin. The chem- A.  pleuropneumoniae, P. multocida, B. bronchiseptica,
ical structure of tildiprosin is characterized by two and H. Parasuis.
piperidine substituents on C20 and C23, and a basic
mycaminose sugar moiety at C5 of the macrocyclic lac- Bibliography
tone ring. Owing to three nitrogen atoms accessible to
protonation, tildipirosin is a tribasic molecule. Menge M, et al. 2012. Pharmacokinetics of tildipirosin in
bovine plasma, lung tissue, and bronchial fluid (from live,
Antimicrobial Activity nonanesthetized cattle). J Vet Pharmacol Ther 35:550.
Tildipirosin is active in vitro against M. haemolytica,
P.  multocida, A. pleuropneumoniae, B. bronchiseptica, Rose M, et al. 2012. Pharmacokinetics of tildipirosin in por-
H. somni, and H. parasuis (Table 13.1). The activity of cine plasma, lung tissue, and bronchial fluid and effects of
tildipirosin against other bacterial pathogens of veteri- test conditions on in vitro activity against reference strains
nary importance has not been studied. and field isolates of Actinobacillus pleuropneumoniae. J Vet
Pharmacol Ther doi:10.1111/j.1365-2885.2012.01397.x.
Pharmacokinetic Properties
The pharmacokinetics of tildipirosin in cattle and swine Tylvalosin
are characterized by rapid absorption from the injection
site, extensive distribution into tissues and slow elimina- Tylvalosin (acetylisovaleryltylosin) is a new 16-membered
tion, which collectively contribute to high and sustained lactone ring macrolide antibiotics recently approved in
concentrations in bronchial fluid, and lung tissue (Rose some countries for use in swine and poultry.
et al., 2012; Menge et al., 2012). The bioavailability of til-
dipirosin after SC administration to cattle is approximately Antimicrobial Activity
80% (Menge et al., 2012). The apparent volume of distri- Tylvalosin is highly active in vitro against Mycoplasma
bution after IV administration to cattle is 49 L/kg (Menge synoviae (Cerdá et al., 2002), M. hyopneumoniae, and
et al., 2012). Peak lung concentrations are approximately M. gallisepticum. It is also active against some but not
15 (Menge et al., 2012; Rose et al., 2012;) and 4 μg/g after all isolates of Brachyspira hyodysenteriae and Brachyspira
administration of a dose of 4 mg/kg to cattle and swine, pilosicoli (Pringle et al., 2012). In vitro suscep-
respectively (Menge et al., 2012; Rose et al., 2012). tibility  data  on a limited number of isolates indicate
that the  drug is active against some obligate anaer-
Toxicity and Adverse Effects obes  (e.g.,  Bifidobacterium spp. Clostridium spp.,
Tildipirosin is safe to use in cattle. No serious adverse Eubacterium spp. Peptostrectococcus spp. and Bacteroides
events were noted during the clinical development pro- spp.). Tylvalosin is not active against enteric Gram-negative
gram of the drug. Mild to moderate injection site swell- bacteria. The activity of tylvalosin against many bacterial
ing and pain on palpation of the injection site are pathogens of veterinary importance has not been
common in treated cattle and swine. During clinical tri- studied.
als in swine, treatment with tildipirosin caused shock
symptoms in 2 of 1048 treated animals. Safety has not Pharmacokinetic Properties
been assessed in other species. Tylvalosin tartrate is rapidly absorbed after oral admin-
istration to pigs and chicken. Tylvalosin is rapidly
Administration and Dosage metabolized to 3-O-acetyltylosin, which possesses
Administration and dosages are summarized in Table 13.2. equivalent microbiological activity to the parent
compound.

Chapter 13. Macrolides, Azalides, and Ketolides 227

In pigs, plasma concentrations are below the limit of Other Classic Macrolides
quantification after administration of the recommended
dose. Uncommon macrolide antibiotics (oleandomycin, josa-
mycin, kitasamycin, rosaramicin) have activity similar
In chickens, peak plasma concentrations are achieved to erythromycin, spiramycin, and tylosin. There is little
approximately 1 hour after a single oral dose. Tylvalosin reported experience with their use in veterinary medi-
is rapidly distributed to the major organs. In pigs, highest cine, although kitasamycin is used in Japan. The agents
concentrations are found in bile, spleen, lung, kidney appear to have nothing to offer over the commonly used
and liver. Tylvalosin concentrations in the lung are classic macrolide antibiotics.
detected for up to 12 hours after administration. Part of
the overall efficacy of the product might be due to the Advanced-Generation Macrolide Antibiotics:
activity of the metabolites rather than to tylvalosin alone. Roxithromycin, Clarithromycin, and
Azithromycin
Toxicity and Adverse Effects
No adverse reactions related to the drug were observed Interest in the macrolides has been stimulated by their
during clinical or target animal safety studies. activity against traditional and emerging human patho-
gens, including Campylobacter spp., Helicobacter spp.,
Administration and Dosage Legionella spp., as well as against intracellular organisms
Administration and dosages are summarized in that have emerged through the AIDS epidemic, such as
Table 13.2. Bartonella spp. and Mycobacterium spp. Newer erythro-
mycin derivatives with enhanced pharmacokinetic and
Clinical Applications in some cases broader antibacterial activities include
Poultry. In some countries, tylvalosin tartrate is roxithromycin, dirithromycin, clarithromycin, and
approved for the prevention and treatment of azithromycin.
Mycoplasmosis (M. gallisepticum, M. synoviae and other
Mycoplasma spp.) and diseases associated with Roxithromycin is an acid-stable derivative of erythro-
Clostridium perfringens in chickens and turkeys. The mycin with similar activity to erythromycin and com-
drug is also indicated for prevention and treatment of plete cross-resistance with erythromycin. Roxithromycin
Mycoplasmosis in pheasants. differs from erythromycin by an improved pharmaco-
logical profile characterized by enhanced oral bioavaila-
Swine. In the United States, tylvalosin tartrate is bility and longer half-life, allowing for once- or twice-daily
approved for the control of porcine proliferative enteri- administration. It is a well-tolerated alternative to eryth-
tis associated with Lawsonia intracellularis infection. In romycin for daily oral administration. Dirithromycin has
many other countries, the drug is also approved for the similar in vitro activity as erythromycin but offers the
treatment and prevention of porcine proliferative enter- advantage of once-daily dosage. Dirithromycin is no
opathy (Guedes et al., 2009), swine enzootic pneumonia longer available in the United States.
caused by susceptible strains of M. hyopneumoniae, and
swine dysentery caused by B. hyodysenteriae. Clarithromycin, a 6-0-methyl derivative of erythro-
mycin, is approximately twice as active as erythromycin
Bibliography against bacteria on a weight basis, has a half-life about
twice that of erythromycin, and includes good activity
Cerdá RO, et al. 2002. In vitro antibiotic susceptibility of field against Mycobacterium avium. Azithromycin, an acid-
isolates of Mycoplasma synoviae in Argentina. Avian Dis stable  15-membered ring azalide, is more active than
46:215. erythromycin against Gram-negative bacteria and also
has a considerably lengthened half-life relative to eryth-
Guedes RMC. 2009. Use of tylvalosin-medicated feed to con- romycin. The application of these and other newer mac-
trol porcine proliferative enteropathy. Vet Rec 165:342. rolides for veterinary use will likely take advantage of
their long half-lives, which may allow for a single
Pringle M, et al. 2012. Antimicrobial susceptibility of porcine administration in the treatment of infections caused by
Brachyspira hyodysenteriae and Brachyspira pilosicoli isolated
in Sweden between 1990 and 2010. Acta Vet Scand 21 54:54.

228 Section II. Classes of Antimicrobial Agents

pathogens such as Campylobacter and Mycoplasma, and Leptospira, Mycoplasma, members of the Spirochetaceae,
of infections caused by intracellular bacteria. and Ureaplasma. Mycobacteria such as M. avium are
often moderately susceptible. Activity against anaerobic
Antimicrobial Activity bacteria is variable (Table 13.3).

Bacteria with MIC ≤ 2 μg/ml are generally regarded as Pharmacokinetic Properties
susceptible and ≥ 8 μg/ml as resistant to newer mac-
rolides. All these macrolides approved for use in human In comparison to erythromycin, from which they have
medicine share similar antibacterial spectrum of activity been developed, newer macrolides are acid stable, pro-
against Gram-positive isolates with clarithromycin being duce fewer gastrointestinal adverse effects, have higher
the most active against Rhodococcus equi (Table  13.3). bioavailability following oral administration, have con-
Azithromycin has the broadest in vitro spectrum against siderably lengthened serum half-lives, and produce
Gram-negative bacteria, including moderate activity higher tissue concentrations, so that single or twice daily
against Salmonella enterica, but the others also have dosing is appropriate. Oral bioavailability of azithromy-
activity against important human upper respiratory cin is approximately 97% in dogs and about 50% in cats
tract  Gram-negative pathogens (Bordetella pertussis, and foals. The oral bioavailability of clarithromycin in
Haemophilus influenzae, and Moraxella catarrhalis). dogs is lower, ranging between 60 and 80%. The bioa-
Other important antibacterial effects includes excellent vailability of clarithromycin in dogs is not significantly
activity against the genera Bartonella, Borrelia, Brucella, influenced by feeding (Vilmanyi et al., 1996). Azith-
Campylobacter, Chlamydia (trachomatis), Legionella, romycin but not clarithromycin, is also available as an

Table 13.3. In vitro activity (MIC90) of erythromycin and newer macrolides (μg/ml) against selected
bacterial pathogens.

Organisms Erythromycin Roxithromycin Clarithromycin Azithromycin

Gram-positive aerobes ≤ 0.016 ≤ 0.03 ≤ 0.016 ≤ 0.016
Arcanobacterium pyogenes 0.03 0.13 0.06 0.03
Erysipelothrix rhusiopathiae 0.25 0.5 0.13 1
Listeria monocytogenes 0.5* 0.25* 0.06* 1*
Rhodococcus equi 0.25 0.25 0.25 0.25
Staphylococcus aureus 0.13 0.13 0.06 0.13
Streptococcus agalactiae ≤ 0.25 ≤ 0.06 ≤ 0.12
S. equi (subsp. equi and zooepidemicus) 4
>4 16 >4 >8
Gram-negative aerobes >4 0.13 >4 >8
Escherichia coli >4 2 >4 4
Klebsiella spp. 4 0.125 2 1
Salmonella enterica 1 1 0.25
Pasteurella multocida 16 16 8 2
Pasteurella spp. (equine) > 32
Brucella spp. 0.13 0.03 0.016
2 2 0.5
Gram-negative: other 0.5 1 0.25
Bartonella henselae
Campylobacter spp. >8 16 4
Helicobacter pylori 4 4 4
16 8 1
Anaerobes > 32 > 32 > 32
Bacteroides fragilis
Clostridium perfringens
Fusobacterium necrophorum
Peptostreptococcus spp.

*Resistance has been documented.

Chapter 13. Macrolides, Azalides, and Ketolides 229

IV formulation. Serum elimination half-lives are 20 Clinical Applications
hours and 35 hours for azithromycin in foals and cats,
respectively. The elimination half-life of clarithromycin There is limited experience with the use of newer mac-
in foals (4.8 hours) is shorter than that of azithromycin rolides in veterinary medicine, but these drugs offer the
but longer than that of erythromycin (1 hour). The long advantage for monogastrates of better oral bioavailabil-
half-lives of these newer drugs, which is particularly ity, potentially fewer adverse effects, and less frequent
marked for azithromycin, apparently results from exten- administration compared to erythromycin. Their par-
sive uptake by, and slow release from, tissues rather than ticular efficacy against intracellular organisms is a con-
resulting from delayed metabolism. The major route siderable advantage. Potential applications include those
of  excretion is the bile and intestinal tract, although described for erythromycin. For example, as an alterna-
clarithromycin is more markedly excreted through the tive to penicillin in penicillin-allergic animals for the
kidney. About half the administered azithromycin is treatment of infections caused by susceptible Gram-
excreted unchanged in the bile in dogs and cats. Tissue positive aerobes, an alternative to ampicillin or amoxy-
half-lives in cats vary from 13 hours in fat to 72 hours in cillin in the treatment of leptospirosis, and an alternative
heart muscle (Hunter et al., 1995). Concentrations of to tetracyclines in treatment of Rickettsia and Coxiella
azithromycin in the lung and spleen of cats exceeded infections. Newer macrolides may have advantage in the
1  μg/ml 72 hours after a single oral dose of 5.4 mg/kg treatment of intracellular infections in monogastrates,
(Hunter et al., 1995). Tissue concentrations of azithro- including Bartonella, Chlamydophila psittaci and atypical
mycin are generally 10–100 times those achieved in mycobacterial infections. Clarithromycin is effective in
serum. The extensive tissue distribution of azithromycin the treatment of atypical Mycobacterium infections,
appears to result from its concentration within mac- when combined with other antibiotics. Other areas that
rophages and neutrophils. The half-life of azithromycin need to be investigated are use against Mycoplasma infec-
in foal neutrophils is 49 hours (Davis et al., 2002). tions in animals, since medically important Mycoplasma
Bronchoalveolar cells and pulmonary epithelial lining are highly susceptible to clarithromycin in vitro.
fluid concentrations in foals are 15- to 170-fold and 1- to
16-fold higher than concurrent serum concentrations, Dogs and Cats
respectively (Jacks et al., 2001). In foals, clarithromycin Azithromycin in combination with atovaquone was
achieves considerably greater concentrations in pulmo- effective in eliminating Babesia gibsoni from persistently
nary epithelial lining fluid and alveolar macrophages infected dogs (Birkenheuer et al., 2004). Administration
than either erythromycin or azithromycin. However, the of azithromycin to dogs with experimental Rocky
half-life of clarithromycin at these sites is much shorter Mountain spotted fever resulted in improvement of
than that of azithromycin (Suarez-Mier et al., 2007). most of the clinical signs but was not as effective as dox-
ycyline or trovafloxacin in decreasing vascular injury
Toxicity and Adverse Effects to  the eye and clearing viable circulating rickettsiae
(Breitschwerdt et al., 1999). Azithromycin prevented or
In humans, newer macrolides are typically well tolerated resolved episodes of acute arthritis and reduced the bac-
and cause less gastrointestinal disturbances than eryth- terial load but failed to eliminate Borrelia burgdorferi in
romycin. The limited experience in dogs and cats sug- infected dogs (Straubinger, 2000). Azithromycin, given
gest the same to be true in these species. As with earlier at a dose of 10–15 mg/kg daily for 3 days and then twice
macrolides, these drugs occasionally can induce entero- weekly, provided a similar rapid resolution of clinical
colitis in foals. Adult horses appear to have a higher inci- signs when compared to doxycycline in cats with
dence of enterocolitis associated with administration of Chlamydophila felis infections. However, as opposed to
macrolides than foals. Clarithromycin may be fetotoxic doxycycline, azithromycin was ineffective in clearing
and should not be administered to pregnant animals. infection (Owen et al., 2003). In a prospective, rand-
omized, placebo-controlled clinical trial, azithromycin
Administration and Dosage at a dose of 10 mg/kg PO once daily was found to be safe
and effective for the treatment of papillomatosis in dogs
Dosage recommendations for dogs, cats, and foals are
summarized in Table 13.2.

230 Section II. Classes of Antimicrobial Agents

(Yağci et al., 2008). Clarithromycin, in combination with Lavy E, et al. 1995. Minimal inhibitory concentrations for
amoxicillin and a proton pump inhibitor, has been used canine isolates and oral absorption of roxithromycin in fed
successfully for the treatment of gastric ulcers associated and fasted dogs. J Vet Pharm Ther 18:382.
with Helicobacter spp. in dogs (Anacleto et al., 2011).
Owen WM, et al. 2003. Efficacy of azithromycin for the treat-
Horses ment of feline chlamydophilosis. J Feline Med Surg 5:305.
The main indication for the use of azithromycin or
clarithromycin in the horse is for the treatment of Peters J, et al. 2011. Oral absorption of clarithromycin is
Rhodococcus equi infections in foals. The combination nearly abolished by chronic comedication of rifampicin in
of clarithromycin-rifampin is more effective than eryth- foals. Drug Metab Dispos 39:1643.
romycin-rifampin or azithromycin-rifampin especially
in severely affected foals (Giguère et al., 2004). The inci- Peters J, et al. 2012. Clarithromycin is absorbed by an intesti-
dence of diarrhea in foals treated with clarithromycin is nal uptake mechanism which is sensitive to major inhibi-
similar to that observed with erythromycin. In most tion by rifampicin—results of a short-time drug interaction
cases, diarrhea is mild and self-limiting. However, diar- study in foals. Drug Metab Dispos 40:522.
rheic foals should be monitored carefully because some
may develop depression and severe diarrhea, leading to Straubinger RK. 2000. PCR-based quantification of Borrelia
dehydration and electrolyte loss. Clarithromycin and burgdorferi organisms in canine tissues over a 500-day
azithromycin, just like erythromycin, should only be postinfection period. J Clin Microbiol 38:2191.
used when no other alternatives are available in adult
horses because of the potential for severe enterocolitis. Suarez-Mier G, et al. 2007. Pulmonary disposition of eryth-
Concurrent administration of rifampin considerably romycin, azithromycin, and clarithromycin in foals. J Vet
reduces absorption of clarithromycin in foals possibly Pharmacol Ther 30:109.
by inhibition of an unknown intestinal uptake trans-
porter (Peters et al., 2011; Peters et al., 2012). Vilmanyi E, et al. 1996. Clarithromycin pharmacokinetics
after oral administration with or without fasting in cross-
Bibliography bred beagles. J Small Anim Pract 37:535.

Anacleto TP, et al. 2011. Studies of distribution and recur- Yağci BB, et al. 2008. Azithromycin therapy of papillomatosis
rence of Helicobacter spp. gastric mucosa of dogs after tri- in dogs: a prospective, randomized, double-blinded,
ple therapy. Acta Cir Bras 26:82. placebo-controlled clinical trial. Vet Dermatol 19:194.

Birkenheuer AJ. 2004. Efficacy of combined atovaquone and Ketolides
azithromycin for therapy of chronic Babesia gibsoni (Asian
genotype) infections in dogs. J Vet Intern Med 18:494. Ketolides are members of a new semisynthetic 14-
membered ring macrolide, with a 3-keto group instead
Breitschwerdt EB, et al. 1999. Efficacy of doxycycline, of an α-L-cladinose on the erythronolide A ring. The
azithromycin, or trovafloxacin for treatment of experi- two most widely studied ketolides are telithromycin and
mental Rocky Mountain spotted fever in dogs. Antimicrob cethromycin. Both have been developed for oral use.
Agents Chemother 43:813. Their spectrum of activity is similar to that of the newer-
generation macrolides. However, they offer the advan-
Davis JL, et al. 2002. Pharmacokinetics of azithromycin in tage of overcoming some, but not all, of the current
foals after i.v. and oral dose and disposition into phago- mechanisms of resistance to standard macrolides within
cytes. J Vet Pharmacol Ther 25:99. Gram-positive cocci. In general, Staphylococcus aureus
and Streptococcus pyogenes strains with inducible MLSB
Giguère S, et al. 2004. Retrospective comparison of azithromycin, resistance are susceptible to ketolides whereas strains
clarithromycin, and erythromycin for the treatment of foals with constitutive expression of MLSB are resistant.
with Rhodococcus equi pneumonia. J Vet Intern Med 18:568. Conversely, constitutively resistant Streptococcus pneu-
moniae retains high susceptibility to ketolides. Ketolides
Hunter RP, et al. 1995. Pharmacokinetics, oral bioavailability and tis- are also active against most Gram-positive isolates that
sue distribution of azithromycin in cats. J Vet Pharm Ther 18:38. are resistant to macrolides because of macrolide efflux
(mef) genes. The pharmacokinetics properties of
Jacks S, et al. 2001. Pharmacokinetics of azithromycin and ketolides include a long half-life as well as extensive tis-
concentration in body fluids and bronchoalveolar cells in sue distribution and uptake into respiratory tissues and
foals. Am J Vet Res 62:1870. fluids, allowing for once-daily dosing. Adverse effects of
ketolides in humans are similar to those of macrolides
and usually related to the gastrointestinal tract with

Chapter 13. Macrolides, Azalides, and Ketolides 231

diarrhea, nausea, and abdominal pain being the most more active than traditional macrolides against
frequently reported. Albeit rare, cases of fulminant hep- macrolide-resistant R.  equi (Javsicas et al., 2010).
atitis and hepatic necrosis have been reported during However, the MIC90 of telithromycin for macrolide-
therapy with telithromycin in humans. The major indi- resistant R. equi isolates (8 μg/mL) was significantly
cation for the use of ketolides in human medicine is in higher than that of macrolide-susceptible isolates
the treatment of community-acquired pneumonia (0.25 μg /mL), indicating that at least 1 macrolide-
caused by erythromycin-resistant Gram-positive iso- resistance mechanism in R. equi likely confers
lates. Clinical trials focusing on respiratory infections resistance to ketolides as well.
indicate bacteriological and clinical cure rates similar to
comparators, even in patients infected with macrolide- Bibliography
resistant strains.
Blasi F, et al. 2010. Telithromycin. In: Crowe SM, et al. (eds).
Horses Kucers’ the Use of Antibiotics, 6th ed. London: Hodder-
Arnold, p. 825.
The recent increase in resistance to macrolides
amongst isolates of R. equi has led to the investigation File TM. 2005. Telithromycin new product overview. J
of the pharmacokinetics of telithromycin in foals and Allergy Clin Immunol 115(2):S1.
of its in vitro activity against macrolide-susceptible
and macrolide-resistant R. equi isolates. The pharma- Javsicas LH, et al. 2010. Disposition of oral telithromycin in
cokinetic profile of telithromycin in foals is similar to foals and in vitro activity of the drug against macrolide-
that of clarithromycin and azithromycin with accu- susceptible and macrolide-resistant Rhodococcus equi iso-
mulation in pulmonary epithelial lining fluid and lates. J Vet Pharmacol Ther 33:383.
bronchoalveolar cells. Telithromycin was significantly
Zhanel GG, et al. 2003. Ketolides: an emerging treatment for
macrolide-resistant respiratory infections, focusing on
S. pneumoniae. Expert Opin Emerg Drugs 8:297.

Aminoglycosides and Aminocyclitols 14

Patricia M. Dowling

General Considerations cules are also referred to as aminocyclitols or aminoglyco-
sidic aminocyclitols. The aminoglycosides can be divided
The aminoglycosides and aminocyclitols are bactericidal into 4 groups on the basis of the type and substitution
antibiotics primarily used to treat serious infections caused pattern of their aminocyclitol molecule: derivatives con-
by aerobic Gram-negative bacteria and staphylococci. taining the aminocyclitol streptidine (e.g., streptomycin
Amikacin and tobramycin have excellent activity against and dihydrostreptomycin), derivatives containing the
Pseudomonas aeruginosa. However, the use of aminogly- aminocyclitol streptamine (e.g., spectinomycin), deriva-
cosides and aminocyclitols has been eclipsed by the devel- tives containing a 4,5-disubstituted deoxystreptamine
opment of fluoroquinolones, which have better safety moiety (e.g., neomycin), and derivatives containing a
profiles and better distribution kinetics. Renal accumula- 4,6-disubstituted deoxystreptamine moiety (e.g., gen-
tion of aminoglycosides results in detectable drug residues tamicin, kanamycin, amikacin, tobramycin).
for prolonged periods, so their extra-label use in food ani-
mals is strongly discouraged. Nevertheless, they remain Mechanism of Action
important drugs in the treatment of severe Gram-negative
sepsis, although their highly cationic, polar nature means Aminoglycosides must penetrate bacteria to assert their
that distribution across membranes is limited. Single daily effect. Penetration can be enhanced by the presence of a
dosing is now recommended for most dosage regimens as drug that interferes with cell wall synthesis, such
it maximizes efficacy and reduces toxicity. as a beta-lactam antibiotic. Susceptible, aerobic Gram-
negative bacteria actively pump the aminoglycoside into
Chemistry the cell. This is initiated by an oxygen-dependent inter-
action between the antibiotic cations and the negatively
The aminoglycoside antibiotics—streptomycin, dihydros- charged ions of the bacterial membrane lipopolysaccha-
treptomycin, kanamycin, gentamicin, tobramycin, amika- rides. This interaction displaces divalent cations (Ca++,
cin, and neomycin—are large molecules with numerous Mg++), which effects membrane permeability. Once
amino acid groups, making them basic polycations that inside the bacterial cell, aminoglycosides bind to the 30S
are highly ionized at physiological pHs. Their polarity ribosomal sub-unit and cause a misreading of the genetic
largely accounts for the pharmacokinetic properties that code, interrupting normal bacterial protein synthesis.
are shared by all members of the group. Chemically, they This leads to changes in the cell membrane permeability,
consist of a hexose nucleus to which amino sugars are resulting in additional antibiotic uptake, further cell
attached by glycosidic linkages. This is why these mole- disruption, and ultimately, cell death.

Antimicrobial Therapy in Veterinary Medicine, Fifth Edition. Edited by Steeve Giguère, John F. Prescott and Patricia M. Dowling.
© 2013 John Wiley & Sons, Inc. Published 2013 by John Wiley & Sons, Inc.

233

234 Section II. Classes of Antimicrobial Agents

The extent and types of misreading vary because aerobic bacteria under anaerobic conditions. They are
different members of the group interact with different active against some Gram-positive bacteria, such as
proteins. Streptomycin acts at a single site but the other Staphylococcus spp. Emerging strains of methicillin-
drugs act at several sites. Other effects of aminoglyco- resistant Staphylococcus aureus (MRSA) and Staphy-
sides include interference with the cellular electron lococcus pseudintermedius (MRSP) typically retain
transport system, induction of RNA breakdown, inhibi- susceptibility to gentamicin and/or amikacin. They are
tion of translation, effects on DNA metabolism, and often effective against enterococci, but therapy against
damage to cell membranes. The bactericidal effect is streptococci is more effective when combined with a
through the formation of abnormal cell membrane beta-lactam antibiotic. Salmonella and Brucella spp.
channels by misread proteins. are intracellular pathogens and are often resistant.
Some mycobacteria, spirochetes and mycoplasma are
Aminoglycoside action is bactericidal, and dose susceptible. In potency, spectrum of activity, and stability
(concentration) dependent. For example, gentamicin to enzymes from plasmid-mediated resistance, amikacin>
concentrations in the range of 0.5–5.0 μg/ml are bacteri- tobramycin ≥ gentamicin > neomycin = kanamycin >
cidal for Gram-positive and some Gram-negative bacteria. streptomycin. Amikacin was developed from kanamy-
At 10–15 μg/ml, gentamicin is effective against the cin and has the broadest spectrum of activity of the ami-
more resistant bacteria such as Pseudomonas aeruginosa, noglycosides. It is effective against Gram-negative strains
Klebsiella pneumoniae, and Proteus mirabilis. The clini- not susceptible to other aminoglycosides because it is
cal implication is that high initial doses increase ionic more resistant to bacterial enzymatic inactivation. It
bonding, which enhances the initial concentration- is  also considered the least nephrotoxic, but it is
dependent phase of rapid antibiotic internalization and less  efficacious against streptococci than gentamicin.
leads to greater immediate bactericidal activity. Human Streptomycin and dihydrostreptomycin are the most
clinical studies demonstrate that proper initial thera- active of these drugs against mycobacteria and Leptospira
peutic doses of aminoglycosides are critical in reducing and the least active against other organisms. The activi-
mortality from Gram-negative septicemia. For antimi- ties of selected aminoglycosides against selected bacteria
crobials whose efficacy is concentration-dependent, and mycoplasma are shown in Table 14.1.
high plasma concentration levels relative to the MIC of
the pathogen (Cmax:MIC ratio, also known as the inhibi- The bactericidal action of the aminoglycosides on
tory quotient or IQ) and the area under the plasma con- aerobic Gram-negative bacteria is markedly influenced
centration-time curve that is above the bacterial MIC by pH, being most active in an alkaline environment.
during the dosage interval (area under the inhibitory Increased local acidity secondary to tissue damage or
curve, AUIC = AUC/MIC) are the major determinants bacterial destruction may explain the failure of amino-
of clinical efficacy. For the aminoglycosides, a Cmax:MIC glycosides to kill usually susceptible pathogens. Another
ratio of 10 is suggested to achieve optimal efficacy factor affecting activity is the presence of purulent debris,
(McKellar et al., 2004). which ionically binds to aminoglycosides and inacti-
vates them. When using an aminoglycoside to treat
The aminoglycosides have a significant post-antibiotic purulent infections (e.g., abscesses), surgical debride-
effect (PAE); the period of time where antimicrobial ment and/or drainage increases efficacy.
concentrations are below the bacterial MIC, but the
antimicrobial-damaged bacteria are more susceptible to Resistance to Aminoglycoside Antibiotics
host defenses (Gilbert, 1991). The duration of the PAE
tends to increase as the initial aminoglycoside concen- Most clinically important resistance to aminoglyco-
tration increases. sides is caused by plasmid-mediated enzymes, broadly
classified as phosphotransferases, acetyltransferases,
Antimicrobial Activity and adenyltransferases. At least 11 enzymes have been
identified that can inactivate aminoglycosides. These
The antibacterial action of the aminoglycosides is enzymes modify the aminoglycosides at their exposed
directed primarily against aerobic, Gram-negative bacte- hydroxyl or amino groups to prevent ribosomal binding.
ria. Because bacterial uptake is oxygen-dependent, They are present in the periplasmic space of bacteria,
they are not active against facultative anaerobes or

Chapter 14. Aminoglycosides and Aminocyclitols 235

Table 14.1. Activity (MIC90) of selected aminoglycosides (μg/ml) against bacterial pathogens.

Organism Streptomycin Neomycin Kanamycin Gentamicin

Gram-positive cocci 32 0.5 4 1
Staphylococcus aureus 128 32 128 64
Streptococcus agalactiae 64 128 32
S. uberis 8
>128 4 64 ≤4
Gram-positive rods <8 4 0.5-4
Arcanobacterium pyogenes ≤0.25 4
Bacillus anthracis 64 2
Corynebacterium >64 >64 ≤0.25
pseudotuberculosis 32 16–32 ≤64
C. renale 0.5 16
Erysipelothrix rhusiopathiae 16 256 16
Listeria monocytogenes 4 0.12 128
Mycobacterium tuberculosis 32 2 16
Nocardia asteroides ≤1 32 ≤0.25
Rhodococcus equi 256 16 4
64 8–16 1
Gram-negative rods 0.25 4 2
Actinobacillus spp. 2 0.5 0.12
Bordetella bronchiseptica >64 4 0.5
Brucella canis 8 >64 2
Campylobacter jejuni 8 8
Escherichia coli 256 2
Histophilus somni 0.5 8 4
Helicobacter pylori 16 4
Klebsiella pneumonia 0.12 0.5
Leptospira spp. >128 32 8
Moraxella bovis
Mannheimia haemolytica >128 32 8
Pasteurella multocida 16–32 8–16 8
Cattle 2
Pigs >16 4 8
Proteus spp. >16 128 8
Pseudomonas aeruginosa >128 >32 0.5
Salmonella spp. >128
Taylorella equigeniatlis 1

Note: Some reports are higher because of resistance. This table is designed partly to illustrate the differences in
quantitative susceptibility among different aminoglycosides.

so that extracellular inactivation of drug does not gentamicin, kanamycin, sulfonamide, streptomycin,
occur. Plasmid-mediated resistance to aminoglyco- tetracycline, and trimethoprim (Pohl et al., 1993).
sides is transferable between bacteria. A single type of Antimicrobial resistance in organisms such as E. coli
plasmid may confer cross-resistance to multiple ami- and Salmonella species is a focus of international
noglycosides and to other unrelated antimicrobials. research due to potential transference of antimicrobial
A single bacterial isolate may have any one of a variety resistance from animal to human pathogens. Because
of combinations of resistance to different antibiotics there are few alternative treatment options, aminogly-
conferred by the particular plasmid it carries. For cosides are increasingly considered in the treatment of
example, one E. coli strain may be simultaneously MRSA and MRSP infections in companion animals
resistant to ampicillin, apramycin, chloramphenicol, (Papich, 2012).

236 Section II. Classes of Antimicrobial Agents

Strains with reduced permeability and consequently poorly lipid soluble and have limited capacity to enter
two- to four-fold increases in MIC may be selected cells and penetrate cellular barriers. These drugs do not
during treatment with aminoglycosides. Such strains readily attain therapeutic concentrations in transcellular
show cross-resistance to all other drugs within the fluids, particularly cerebrospinal and ocular fluid. The
group. Chromosomal mutation resulting in resistance milk-to-plasma equilibrium concentration ratio is
is relatively unimportant except for streptomycin and approximately 0.5. Their apparent volumes of distribu-
dihydrostreptomycin, where it occurs readily, even tion are relatively small (< 0.35 L/kg) and their plasma
during treatment, as a result of a single-step mutation elimination half-lives are short (1–2 hours) in domestic
to high-level resistance. For the other drugs, chromo- animals. Even though these drugs have a small volume
somal resistance develops slowly, because there are of distribution, selective binding to tissues including
many 30S ribosomal binding sites. Resistance to ami- kidney cortex occurs, so that kidney residues persist in
noglycosides is increasingly important in limiting their animals for extensive periods. Gentamicin is distributed
effectiveness. into synovial fluid in normal horses and local inflamma-
tion may increase drug concentrations in the joint and
Both subinhibitory and inhibitory aminoglycoside concentrations may increase with repeated doses.
concentrations produce resistance in bacterial cells sur- Regional perfusion techniques and aminoglycoside-
viving the initial ionic binding (Barclay and Begg, 2001). impregnated polymethyl methacrylate beads are excel-
This first-exposure adaptive resistance is due to lent methods of local delivery that avoid the adverse
decreased aminoglycoside transport into the bacteria. effects of systemic therapy.
Exposure to 1 dose of an aminoglycoside is sufficient to
produce resistant variants of an organism with altered Elimination is entirely by renal excretion (glomerular
metabolism and impaired aminoglycoside uptake. In filtration), and unchanged drug is rapidly excreted in
vitro, animal and clinical studies show that the resist- the urine. Impaired renal function decreases rate of
ance occurs within 1–2 hours of the first dose. The dura- excretion and makes it necessary to adjust the dosage
tion of adaptive resistance relates directly to the half-life interval to prevent accumulation and toxicity. The sig-
of elimination of the aminoglycoside. With normal ami- nificant individual variation in pharmacokinetic param-
noglycoside pharmacokinetics, the resistance may be eters between animals of the same species exacerbates
maximal for up to 16 hours after a single dose, followed problems of toxicity with this drug class (Brown and
by partial return of bacterial susceptibility at 24 hours Riviere, 1991).
and complete recovery at 40 hours. The clinical signifi-
cance of this phenomenon is that frequent dosing or Drug Interactions
constant infusion of an aminoglycoside is less effective
than high-dose, once-daily dosing. Aminoglycosides are commonly additive and some-
times synergistic with beta-lactam drugs. Synergism
Pharmacokinetic Properties does not usually occur in the presence of high-level
plasmid-mediated or chromosomal resistance. The
Aminoglycosides are poorly absorbed from the normal aminoglycosides are synergistic against streptococci,
gastrointestinal tract, but are well absorbed after IM or enterococci, Pseudomonas and other Gram-negative
SC injection. Following parenteral administration, bacteria if combined with beta-lactam antibiotics due
effective concentrations are obtained in synovial, peri- to disruption of the bacterial cell wall by the beta-
lymph, pleural, peritoneal, and pericardial fluid. When lactam antibiotic (Winstanley and Hastings, 1989).
given to neonates or animals with enteritis, oral absorp- Combinations of newer beta-lactam drugs with newer
tion may be significantly increased and result in viola- aminoglycosides provide optimal therapy in seriously
tive tissue residues in food animals. When given by ill, neutropenic patients with bacterial infections.
intrauterine or intramammary infusion to cows, gen- Aminoglycosides are physically incompatible with a
tamicin is well absorbed and results in prolonged tissue number of drugs including many beta-lactams, so they
residues. Aminoglycosides bind to a low extent to should never be mixed in the same syringe. If adminis-
plasma proteins (less than 25%). As they are large mol- tered sequentially through an infusion set, care should
ecules and highly ionized at physiological pHs, they are be taken to flush well between drugs.

Chapter 14. Aminoglycosides and Aminocyclitols 237

Toxicity and Adverse Effects Calcium supplementation reduces the risk of nephro-
toxicity. Nephrotoxicity can also be decreased by feeding
All aminoglycosides can cause varying degrees of oto- the patient a high-protein diet/high-calcium diet such as
toxicity and nephrotoxicity (Table  14.2). Nephrotoxicity alfalfa to large animals and diets higher than 25% pro-
(acute tubular necrosis) is the most common adverse tein to small animals, as protein and calcium cations
effect of aminoglycoside therapy. Neomycin is the most compete with aminoglycoside cations for binding to
nephrotoxic and streptomycin and dihyrostreptomycin renal tubular epithelial cells (Behrend et al., 1994;
are the least nephrotoxic. Amikacin is often recommended Schumacher et al., 1991). High dietary protein also
in critical patients over gentamicin as it is considered less increases glomerular filtration rate and renal blood flow,
nephrotoxic. Uptake and accumulation of aminoglyco- thereby reducing aminoglycoside accumulation.
sides into renal tubular epithelium demonstrates saturable
kinetics. The aminoglycosides enter the renal tubule after Because nephrotoxicity is related to aminoglycoside
filtration through the glomerulus. From the luminal fluid, accumulation in the renal proximal tubular cells, it is
the cationic aminoglycoside molecules bind to anionic logical that peak concentrations are not related to toxic-
phospholipids on the proximal tubular cells. The ami- ity and that longer dosage intervals result in less total
noglycoside is taken into the cell via carrier-mediated drug contact with the renal brush border membrane.
pinocytosis and translocated into cytoplasmic vacuoles, High-dose, once-daily dosing of aminoglycosides is now
which fuse with lysosomes. The drug is sequestered common in human and veterinary medicine; it takes
unchanged in the lysosomes. With additional pinocytosis, advantage of the concentration-dependent killing and
drug continues to accumulate within the lysosomes. The long PAE of these drugs and avoids first exposure adap-
accumulated aminoglycoside interferes with normal lyso- tive resistance and nephrotoxicity (Gilbert, 1991).
somal function and eventually the overloaded lysosomes
swell and rupture. Lysosomal enzymes, phospholipids, Serum concentrations of aminoglycosides can be
and the aminoglycoside are released into the cytosol of monitored to reduce toxicity and to confirm therapeutic
the proximal tubular cell, disrupting other organelles and concentrations (Bucki et al., 2004). To allow for the dis-
causing cell death (Brown et al., 1991; Figure 14.1). tribution phase, blood sampling for the peak concentra-
tion is done at 0.5–1 hour after administration and the
The risk factors for aminoglycoside toxicity include trough sample is usually taken prior to the next dose.
prolonged therapy (> 7–10 days), multiple doses per day, The peak and trough concentrations can then be used to
acidosis and electrolyte disturbances (hypokalemia, estimate the elimination half-life for the individual
hyponatremia), volume depletion (shock, endotoxemia), patient. An increase in the elimination half-life during
concurrent nephrotoxic drug therapy, age (neonates, therapy is a very sensitive indicator of early tubular
geriatrics), preexisting renal disease, and elevated trough insult. If using a once-daily regimen, a blood sample just
concentrations (Mattie et al., 1989). prior to the next dose may be below the recommended
trough concentrations and may even be below the limit
Table 14.2. Relative risks of toxicity of different of detection of the assay. For these patients, an 8-hour
aminoglycosides at usual dosage. post-dose sample will provide a more accurate estimate
of the elimination half-life. Serum concentrations of
Vestibular Cochlear Renal drug should be 0.5–2 μg/ml before the next dose (gen-
tamicin, tobramycin) or less than 6 μg/ml for amikacin.
Drug Toxicity Toxicity Toxicity
If therapeutic drug monitoring is unavailable, then
Streptomycin +++ ++ (+) nephrotoxicity is detected by an increase in urine
++ +++ (+) gamma glutamyl transferase (GGT) enzyme and an
Dihydrostreptomycin + +++ +++ increase in the urine GGT:urine creatinine (Cr) ratio
Neomycin + ++ ++ (van der Harst et al., 2005). The UGGT:UCr may
Kanamycin (+) increase to 2–3 times baseline within 3 days of a nephro-
Amikacin ++ + ++ toxic dose. If these tests are not available, the develop-
Gentamicin (+) + ++ ment of proteinuria is the next best indicator of
Tobramycin (+) (+) nephrotoxicity and it is easily determined in a practice

Reprinted with permission from Pilloud (1983).

238 Section II. Classes of Antimicrobial Agents

Tubular lumen Renal tubule epithelial cell

Ruptured
lysosome

Brush border

Aminoglycoside Lysosome
cations

Tubular lumen with
aminoglycoside cations

Phospholipid anions

Cell lumen

Figure 14.1. Aminoglycoside cations interact with phospholipid anions on the brush border of renal tubule epithelial cells.
Then they are pinocytosed and accumulate in lysosomes until they cause the lysosome to rupture, which destroys the cell.

setting. Elevations in serum urea nitrogen and Cr con- vestibular (balance) and cochlear (hearing) functions
firm nephrotoxicity, but are not seen for 7 days after equally. This drug-specific toxicity may be due to the
significant renal damage has occurred. Elimination distribution characteristics of each drug and concentra-
half-lives of 24–45 hours have been reported in horses tion achieved in each sensory organ. The ototoxic effect
with renal toxicity, further prolonging the toxic expo- of aminoglycosides is potentiated by the loop diuretics
sure to the drug. While peritoneal dialysis is useful in furosemide and ethacrynic acid and probably other
lowering creatinine and serum urea nitrates, it may not diuretic agents.
be effective in significantly increasing the elimination of
the accumulating aminoglycoside. The animal’s ability All aminoglycosides given rapidly IV cause brady-
to recover most likely depends on the type of medica- cardia, reduce cardiac output, and lower blood pressure
tion exposure and the amount of healthy renal tissue through an effect on calcium metabolism. These effects
remaining to compensate. are of minor significance (Hague et al., 1997). Neuro-
muscular blockade is a rare effect, related to blockade of
Aminoglycoside ototoxicity occurs from the same acetylcholine at the nicotinic cholinergic receptor. Is
mechanisms as nephrotoxicity. The tendency to pro- most often seen when anesthetic agents are administered
duce vestibular damage (streptomycin, gentamicin) or concurrently with aminoglycosides. Affected patients
cochlear damage (amikacin, kanamycin, neomycin) should be treated promptly with parenteral calcium
varies with the drug. Tobramycin appears to affect both chloride at 10–20 mg/kg IV or calcium gluconate at

Chapter 14. Aminoglycosides and Aminocyclitols 239

30–60 mg/kg IV or neostigmine at 100–200 μg/kg to of severe sepsis caused by Gram-negative aerobes and
reverse dyspnea from muscle response depression. increasingly, the treatment of methicillin-resistant
Edrophonium at 0.5 mg/kg IV will also reverse neuro- staphylococcal infections. Of these, gentamicin is
muscular blocking effects. usually the first choice followed by amikacin, which
due  to expense is reserved for sepsis caused by
Dosage Considerations organisms resistant to gentamicin. But even the expen-
sive  aminoglycosides can be used for local therapy of
Aminoglycosides produce rapid, concentration-dependent musculoskeletal infections. Antimicrobial impregnated
killing of Gram-negative aerobes and a prolonged polymethyl methacrylate beads, collagen sponges and
PAE (McKellar, et al., 2004). Therefore, the maximum regional perfusion (intravenous or intraosseous) pro-
plasma concentration (Cmax) to MIC ratio determines vide high local concentrations with less expense and less
efficacy. A Cmax:MIC ratio of 8–12:1 optimizes bacteri- risk of systemic toxicity.
cidal activity. Higher initial serum concentrations may
also be associated with a longer PAE. Traditionally, Because aminoglycoside residues persist in renal
aminoglycosides were administered every 8–12 hours. tissues for prolonged periods, the extra-label use in food
If the aminoglycoside is dosed multiple times a day or animals should be avoided. A voluntary resolution
the drug concentration remains constant, as with a against the extra-label administration of aminoglyco-
continuous infusion, first exposure adaptive resistance sides has been adopted by the American Association of
persists and increases and the risks of nephrotoxicity Bovine Practitioners, the Academy of Veterinary
and ototoxicity increases. Dose administration at Consultants, the National Cattlemen’s Beef Association
24-hour intervals, or longer, may increase efficacy by and the American Veterinary Medical Association.
allowing time for adaptive resistance to reverse. Some
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from human and animal sources in Belgium. Epidemiol effect. They are commonly synergistic with cell wall
Infect 111:229. active antibiotics such as penicillin, and combination
formulations were once available. This synergism occurs
Schumacher J, et al. 1991. Effect of diet on gentamicin-induced against Gram-positive bacteria such as streptococci,
nephrotoxicosis in horses. Am J Vet Res 52:1274. which are otherwise impermeable to the drug, and in
bacteria with chromosomal mutation to low-level resist-
Van der Harst MR, et al. 2005. Gentamicin nephrotoxicity—a ance. Synergism does not usually occur in the presence
comparison of in vitro findings with in vivo experiments of high-level plasmid or chromosomal resistance or in
in equines. Vet Res Commun 29:247. Gram-negative bacteria.

Winstanley TG, Hastings JG. 1989. Penicillin-aminoglycoside Toxicity and Adverse Effects
synergy and post-antibiotic effect for enterococci. J Antimicrob
Chemother 23:189. Besides resistance, toxicity limits the use of streptomy-
cin and dihyrdrostreptomycin. They cause vestibular
Streptomycin/Dihydrostreptomycin damage—an effect that increases with the daily and
cumulative dose, with the height of peak serum concen-
Streptomycin and dihydrostreptomycin are members of trations, and with preexisting renal disease. In general,
the streptidine group. Dihydrostreptomycin has very no toxic effects occur if streptomycin is used at recom-
similar properties to streptomycin but is more likely to mended doses for up to 1 week. Streptomycin can cause
cause deafness. Streptomycin was the earliest aminogly- permanent vestibular damage, producing ataxia that
coside introduced for clinical use. progresses to incoordination, nystagmus, loss of right-
ing reflex, and death. The effects are dose related. Daily
Antimicrobial Activity IM injections of doses 5–10 times those recommended
produce this effect in cats in about 10 days. Cats are par-
Streptomycin and dihyrdrostreptomycin are active against ticularly sensitive to streptomycin and usual doses may
mycobacteria, some mycoplasma, some Gram-negative produce nausea, vomiting, salivation, and ataxia.
rods (including Brucella), and some Staphylococcus aureus.
With the exception of mycobacteria, streptomycin is the Neuromuscular blockade is produced when strep-
least active of the aminoglycosides. Among susceptible tomycin is given at high doses. Although this effect is
bacteria are Leptospira, Francisella tularensis, Yersinia insignificant at normal doses, deaths have occurred in
pestis, and most Campylobacter fetus ssp. venerealis dogs and cats given high doses of penicillin-streptomycin
(Table 14.1). Organisms with MIC ≤4μg/ml are regarded combinations for prophylaxis of surgical infection
as susceptible. after general anesthesia, since general anesthetics
and  muscle relaxants potentiate the neuromuscular
Antimicrobial Resistance blocking effects.

Acquired resistance to streptomycin and dihyrdrostrep-
tomycin is widespread in veterinary pathogens and has
virtually eliminated the use of these drugs except for
special applications. Even agricultural use of streptomycin
selects for multidrug-resistant nasal and enteric bacterial
flora, including extended-spectrum beta-lactamase-

Chapter 14. Aminoglycosides and Aminocyclitols 241

Table 14.3. Common dosages of aminoglycosides and aminocyclitols in animals.

Dosage Interval

Drug Route (mg/kg) (h)/Duration Comments

Amikacin IU 2g 24 × 3 days Metritis in mares
IV, IM, SC 10 24 × 5–7 days Gram-negative infections in adult horses
Apramycin IV, IM, SC 20–25 24 × 5–7 days Gram-negative infections in neonatal foals
Dihydrostreptomycin PO 12.5 24 × 7 days Colibacillosis in swine
Gentamicin IM 20 12–24 × 5 days Salmonellosis in calves
IM 12.5–15 24 × 3–5 days Leptospirosis in cattle, swine, and dogs
Kanamycin IU 2.0–2.5 g 24 × 3–5 days Metritis in mares
Neomycin IV, IM, SC 4–6 24 × 5–7 days Gram-negative infections in adult horses, dogs, cats
Spectinomycin IV, IM, SC 10–14 24 × 5–7 days Gram-negative infections in neonatal foals
PO 10 mg/kg 8 × 5 days Enteric infections in dogs
Spectinomycin with lincomycin PO 4.5–12 24 × 3–14 days Enteric infections. Efficacy limited due to resistance
Streptomycin PO 20–40 24 × 3–5 days Colibacillosis in swine, chronic respiratory disease in chickens
SC 11–22 Once Fowl cholera in turkeys
SC 10 24 × 3–5 days Bovine respiratory disease
SC 20 12–24 × 3–21 days Bacterial infections in dogs and cats
PO 10 mg/kg 24 × 3–5 days Enteric infections in chickens, swine, and calves. Efficacy
limited due to resistance

Administration and Dosage also were effective for resolving leptospirosis and may
be useful substitutes for dihydrostreptomycin, as it is
Streptomycin is only available in the United States as an no longer available for use in food-producing animals
oral sulfate solution administered in drinking water of in the United States or Canada as a parenteral product.
chickens, swine and calves. In the United States and An experimental and a field study showed that either
Canada, dihydrostreptomycin is only available in single or 5-day treatment of streptomycin in cows
intramammary formulations along with procaine peni- experimentally infected with L. hardjo was effective in
cillin G. In Europe, streptomycin is available as an stopping shedding for at least 70 days after treatment
injectable product alone, and in combination with dihy- (Gerritsen et al., 1994; Gerritsen et al., 1993). But
drostreptomycin. Dosages of streptomycin and dihy- injectable streptomycin is no longer available in the
rdrostreptomycin are shown in Table 14.3. United States or Canada.

Clinical Applications Swine
Dihydrostreptomycin/penicillin G is effective for
Dihyrdrostreptomycin or streptomycin is used in the treatment of acute and persistent leptospirosis in
treatment of leptospirosis in cattle, swine and dogs. swine when given at higher than label doses (Alt and
Streptomycin is rarely used alone for infections in Bolin, 1996). This regimen may be useful for treat-
animals because of widespread resistance, particularly in ment of breeding stock or animals destined for
Gram-negative bacteria and the penicillin combination import/export.
products are no longer available. The newer aminoglyco-
sides are more active against a greater number of organ- Dogs and Cats
isms and are less toxic. There seems to be little place for streptomycin in infec-
tions of dogs, other than as part of combination therapy
Cattle, Sheep, and Goats in for brucellosis (Ledbetter et al., 2009). Streptomycin
Leptospirosis in cattle can be successfully treated should not be used in cats.
by administration of dihydrostreptomycin-penicillin G
(Alt et al., 2001). Oxytetracycline, tilmicosin, and ceftiofur

242 Section II. Classes of Antimicrobial Agents

Poultry commensals and pathogens but less common among
Streptomycin is sometimes used in oral treatment of non- other opportunist pathogens.
specific enteritis in chickens and, combined with penicil-
lin, in the parenteral treatment of erysipelas in turkeys. Drug Interactions

Bibliography Neomycin shows in vitro synergistic activity with beta-
lactam antibiotics and bacitracin against Gram-positive
Alt DP, Bolin CA. 1996. Preliminary evaluation of antimicrobial bacteria, and it is commonly included in topical,
agents for treatment of Leptospira interrogans serovar ophthalmic (also as framycetin) and intramammary
pomona infection in hamsters and swine. Am J Vet Res 57:59. products. The combination of EDTA-Tris and neomy-
cin is synergistic against the microorganisms associated
Alt DP, et al. 2001. Evaluation of antibiotics for treatment of with otitis externa in dogs (Sparks et al., 1994).
cattle infected with Leptospira borgpetersenii serovar
hardjo. J Am Vet Med Assoc 219:636. Toxicity and Adverse Effects

Gerritsen MJ, et al. 1993. Effect of streptomycin treatment on Neomycin is the most toxic of the aminoglycosides and
the shedding of and the serologic responses to Leptospira readily causes nephrotoxicity and deafness. It should
interrogans serovar hardjo subtype hardjobovis in experi- never be used parenterally for this reason. Toxic effects
mentally infected cows. Vet Microbiol 38:129. are generally not produced when administered orally or
applied locally, but severe adverse effects of deafness and
Gerritsen MJ, et al. 1994. Effective treatment with dihydros- tubular necrosis have occurred in humans after oral
treptomycin of naturally infected cows shedding Leptospira administration.
interrogans serovar hardjo subtype hardjobovis. Am J Vet
Res 55:339. Cats given high IM doses (100 mg/kg) daily showed
nephrotoxic effects and became deaf in a few days; dogs
Ledbetter EC, et al. 2009. Brucella canis endophthalmitis in are about equally susceptible. When treated for infectious
3 dogs: clinical features, diagnosis, and treatment. Vet enteritis with paramomycin, cats have developed acute
Ophthalmol 12:183. renal failure, deafness and cataracts (Gookin et al., 1999).
Total deafness was described in a dog after administration
Scherer A, et al. 2012. Enhanced antibiotic multi-resistance of 500 mg SC for 5 days (Fowler, 1968). In cattle, parenter-
in nasal and faecal bacteria after agricultural use of strep- ally administered neomycin causes nephrotoxicity and
tomycin. Environ Microbiol 15:297. deafness, which may be enhanced by dehydration. In
pigs, transient posterior paresis and apnea immediately
Dihydrosteptamine Aminoglycosides: after injection have resulted from neuromuscular block-
Neomycin Group ade. In horses, IM administration of 10 mg/kg caused
renal tubular injury (enzymuria and cylindriuria) within
Neomycin is the isomeric mixture of neomycin B and C. 4 days of neomycin administration (Edwards et al., 1989).
Framycetin is identical to neomycin B. Paramomycin
(aminosidine) is closely related to neomycin. Administration and Dosage

Antimicrobial Activity Neomycin is reserved for local treatment of infections,
often combined with bacitracin and polymixinB (“triple
Neomycin has similar activity to kanamycin on a weight antibiotic”) for broad-spectrum synergistic activity.
basis and is several times more active than streptomy- Framycetin is also used in topical ophthalmologic prep-
cin; it is less active than gentamicin, tobramycin, and arations. Neomycin is routinely incorporated into
amikacin. Activity against Staphylococcus aureus is good “over-the-counter” oral formulations for enteritis in
but is generally low against other Gram-positive bacte- animals. These formulations are largely ineffective due
ria (Table  14.1). Many opportunist Gram-negative to widespread resistance in the Enterobacteriaceae. In
pathogens are susceptible to neomycin, although the some countries, neomycin is used as a parenteral injec-
prevalence of susceptible strains is slightly less than for tion for food animals and horses. Because of toxicity, such
kanamycin and far less than for gentamicin. Bacteria usage is strongly discouraged. It is also incorporated into
with an MIC ≤ 8 μg/ml are regarded as susceptible.

Resistance

Plasmid-mediated resistance occurs through a variety
of enzymes. Such resistance, which often confers mul-
tiple drug resistance, is relatively common in enteric

Chapter 14. Aminoglycosides and Aminocyclitols 243

combination formulations for intramammary treatment Horses
of mastitis in dairy cows. Neomycin may be used in the local treatment of infec-
tions caused by susceptible bacteria but is too toxic to
Clinical Applications consider for parenteral administration (Edwards et al.,
1989). Oral administration is suggested for selective
Neomycin is used for the local treatment of intestinal intestinal decontamination in horses with hepatic
infections, of wound, otic, or skin infections, and of encephalopathy.
mastitis. Its relatively broad spectrum of activity and
the bactericidal effect made the drug popular in some Dogs and Cats
countries for parenteral use in farm animals as an inex- Neomycin is used in combination formulations for the
pensive “alternative” to gentamicin. However, safer, con- local treatment of infections in dogs and cats, such as
siderably less toxic, and more efficacious alternate drugs otitis externa, bacterial keratitis and anal sac infections.
are now readily available. Framycetin is found in some Paramomycin has been used in the treatment of crypto-
veterinary ophthalmic formulations. sporidiosis in cats (Barr et al., 1994) and leishmaniasis
in dogs (Oliva et al., 2004; Oliva et al., 1998).
Cattle, Sheep, and Goats
Neomycin is used in the oral treatment of enteric infec- Poultry
tions in ruminants, though resistance increasingly limits Neomycin is sometimes administered orally to chickens
its effectiveness (Constable, 2004; Constable, 2009). and turkeys in the treatment of Salmonella infections.
Shull and Frederick (1978) found that routine addition
of neomycin to milk powder of neonatal calves increased Bibliography
the frequency of diarrhea, possibly through a suppressive
effect on normal intestinal microflora or through an Alali WQ, et al. 2004. Effect of antibiotics in milk replacer
irritant effect on the mucosa and it may increase shed- on  fecal shedding of Escherichia coli O157:H7 in calves.
ding of E. coli O157:H7 (Alali et al., 2004). Neomycin is J Anim Sci 82:2148.
absorbed after oral administration (approximately 3%)
and may lead to kidney residues in cattle, especially veal Barr SC, et al. 1994. Use of paromomycin for treatment of
calves with enteritis (Pedersoli et al., 1994; Wilson et al., cryptosporidiosis in a cat. J Am Vet Med Assoc 205:1742.
1991). Routine intrauterine administration of neomycin
boluses to postparturient cattle significantly increased Constable PD. 2004. Antimicrobial use in the treatment of
the number of services per conception compared to calf diarrhea. J Vet Intern Med 18:8.
controls (Fuquay et al., 1975). Neomycin is commonly
incorporated into intramammary formulations for Constable PD. 2009. Treatment of calf diarrhea: antimicro-
mastitis. But the use of a penicillin G-neomycin combi- bial and ancillary treatments. Vet Clin North Am Food
nation did not increase the efficacy of the treatment Anim Pract 25:101.
over that achieved by using penicillin G alone in bovine
clinical mastitis caused by penicillin-susceptible, Gram- Edwards DJ, et al. 1989. The nephrotoxic potential of neomy-
positive bacteria (Taponen et al., 2003). cin in the horse. Equine Vet J 21:206.

Paromomycin is available in some countries for Fayer R, Ellis W. 1993. Paromomycin is effective as prophylaxis
parenteral use for the treatment of bovine respiratory for cryptosporidiosis in dairy calves. J Parasitol 79:771.
disease. Paramomycin is used in the treatment of acute
cryptosporidiosis caused by Cryptosporidium parvum Fowler NG. 1968. The ototoxicity of neomycin in the dog.
(Fayer and Ellis, 1993; Grinberg et al., 2002) but may be Vet Rec 82:267.
less effective than azithromycin for this purpose.
Fuquay JW, et al. 1975. Routine postpartum treatment
Swine of dairy cattle with intrauterine neomycin sulfate boluses.
Neomycin is used in the oral treatment of E. coli enteritis J Anim Sci 58:1367.
in swine, although resistance increasingly limits its use.
Gookin JL, et al. 1999. Acute renal failure in four cats treated
with paromomycin. J Am Vet Med Assoc 215:1821.

Grinberg A, et al. 2002. Controlling the onset of natural
cryptosporidiosis in calves with paromomycin sulphate.
Vet Rec 151:606.

Oliva G, et al. 1998. Comparative efficacy of meglumine anti-
moniate and aminosidine sulphate, alone or in combination,
in canine leishmaniasis. Ann Trop Med Parasitol 92:165.

Oliva G, et al. 2004. [Canine leishmaniasis: evolution of the
chemotherapeutic protocols]. Parassitologia 46:231.

Persoli WM, et al. 1994. Disposition and bioavailability of
neomycin in Holstein calves. J Vet Pharm Ther 17:5.

244 Section II. Classes of Antimicrobial Agents

Shull JJ, Frederick HM. 1978. Adverse effect of oral antibac- Bacteria with an MIC ≤ 16 μg/ml are regarded as
terial prophylaxis and therapy on incidence of neonatal susceptible, of 32 μg/ml as intermediate, and of ≥
calf diarrhea. Vet Med Small Anim Clin 73:924. 64 μg/ml as resistant.

Sparks TA, et al. 1994. Antimicrobial effect of combinations Resistance
of EDTA-Tris and amikacin or neomycin on the microor- Plasmid-mediated resistance can occur through a
ganisms associated with otitis externa in dogs. Vet Res variety of enzymes. Chromosomal resistance develops
Commun 18:241. slowly but is far less important. Cross-resistance occurs
with neomycin and one-way cross-resistance with strep-
Taponen S, et al. 2003. Efficacy of intramammary treatment tomycin. Acquired resistance of Escherichia coli and
with procaine penicillin G vs. procaine penicillin G plus other Gram-negative rods occurs frequently.
neomycin in bovine clinical mastitis caused by penicillin-
susceptible, gram-positive bacteria—a double blind field Toxicity and Adverse Effects
study. J Vet Pharmacol Ther 26:193. Kanamycin has a larger therapeutic index than neomycin
but is less toxic on a weight basis. Although excessively
Wilson DJ, et al. 1991. Detection of antibiotic and sulfona- high doses are toxic to dogs and cats, cats given 100 mg/kg
mide residues in bob veal calf tissues: 967 cases (1987–1988). daily SC over 30 days showed no ill effects, and neither
J Am Vet Med Assoc 199:759. did dogs given the same dose over 9 months (Yeary, 1975).

Kanamycin Group Clinical Applications
Kanamycin has been largely replaced for parenteral
The kanamycin group contains the kanamycins and semi- administration by more active aminoglycosides. For
synthetic derivatives such as amikacin, the nebramycins local applications it offers no advantage over neomycin.
such as tobramycin and apramycin, and gentamicin, Kanamycin is only available in the United States as an
netilmicin, and sisomicin. oral product for bacterial enteritis in dogs in combination
with antidiarrheals, but some injectable formulations
Kanamycin are still available in Europe.

Antimicrobial Activity
Kanamycin (Figure  14.2) has similar activity to
neomycin. It is active against many species of myco-
bacteria and mycoplasma but is inactive against
Pseudomonas aeruginosa and anaerobes (Table  14.1).

12 Bibliography

H2C NH2 NH2 Yeary RA. 1975. Systemic toxic effects of chemotherapeutic
O agents in domestic animals. Vet Clin North Am 5:511.
3 2 NH R
5 O 4 II 1 Amikacin

HO 4 I 1 5 6 CH2 OH Amikacin is a chemical modification of kanamycin
(Figure 14.2), with greater activity than kanamycin, but
32 HO O O5 with similar activity to gentamicin or tobramycin.
Amikacin is remarkable in its resistance to most of the
HO OH 1 III 4 OH enzymes that inactivate the other aminoglycosides. This
3 makes amikacin particularly valuable in the treatment
of Pseudomonas aeruginosa infections.
23
Antimicrobial Activity
HO NH2 Susceptible bacteria (MIC ≤ 16 μg/ml) are the
4 Enterobacteriaceae including gentamicin-resistant

Kanamycin R: H
O OH

Amikacin R: C CH CH2 CH2 NH2

Figure 14.2. Chemical structure of kanamycin.

Chapter 14. Aminoglycosides and Aminocyclitols 245

Enterobacter spp., E. coli, Klebsiella spp., Proteus spp., (Pinto et al., 2011). Protein binding is low. Elimination
and Serratia spp. Among Gram-positive bacteria, half-lives are prolonged in neonates, especially if they
Nocardia spp. and staphylococci are susceptible are septic or hypoxic (Green and Conlon, 1993; Green
(Table 14.4). Veterinary isolates of methicillin-suscepti- et al., 1992; Wichtel et al., 1992). Bioavailability from
ble staphylococci and MRSA and MRSP are typically IM or SC injection is high (90–100%). Amikacin
susceptible (Rubin et al., 2011). Amikacin is typically distributes into peritoneal fluid and synovial fluid
more active than gentamicin against P. aeruginosa, but in horses.
less active against streptococci. Resistant bacteria (MIC ≥
64 μg/ml) include anaerobes, many streptococci and Drug Interactions
enterococci, and some Pseudomonas spp. Amikacin is synergistic with beta-lactams (e.g., azlo-
cillin or ticarcillin) against P. aeruginosa. Synergistic
Antimicrobial Resistance activity is seen when amikacin is combined with
Emergence of resistance to amikacin has been uncom- EDTA-Tris plus amikacin against canine otitis iso-
mon compared to gentamicin and other newer amino- lates of S. pseudintermedius, Proteus mirabilis, P. aer-
glycosides but hospital-associated plasmid-mediated uginosa, and E. coli (Sparks et al., 1994). Combinations
resistance in Gram-negative bacteria has been described of amikacin and erythromycin were antagonistic
(Orsini et al., 1989). Resistance in E. coli isolates is more against Rhodococcus equi isolates in vitro (Giguère
common in companion animals than food animals et al., 2012).
(Davis et al., 2011; Lei et al., 2010).

Pharmacokinetic Properties Toxicity and Adverse Effects
Amikacin’s pharmacokinetic properties are typical for Amikacin may be slightly less nephrotoxic and oto-
an aminoglycoside. Reported volumes of distribution toxic than kanamycin. In animals with normal renal
range from 0.15 to 0.3 L/kg and plasma elimination function, amikacin administered at recommended
half-lives range from 1 to 2 hours in adult animals doses for 2–3 weeks rarely causes toxic effects.
Monitoring renal function during treatment is recom-
Table 14.4. Activity (MIC90) of tobramycin, amikacin, and mended. Concerns that decreased glomerular filtra-
apramycin (μg/ml) against selected bacteria. tion in neonatal foals might lead to a need to reduce
dosage to prevent nephrotoxicity were reported to be
Organism Tobramycin Amikacin Apramycin unfounded by Adland-Davenport et al. (1990), since
renal clearance was greater in foals than in adult
Gram-positive aerobes >32 2 1 horses. Dosage should be adjusted in cases of preexisting
Nocardia spp. 1 ≤0.25 32 renal impairment, preferably guided by therapeutic
Rhodococcus equi 8 drug monitoring.
Staphylococcus aureus 64 4 16
Streptococcus pyogenes 256 16 Administration and Dosage
2 Suggested drug dosages are shown in Table  14.3.
Gram-negative aerobes 2 8 8 Amikacin is labeled for intrauterine use in mares and
Actinobacillus spp. 2 8 4 IM or SC use in dogs. It is frequently administered IV,
Bordetella bronchiseptica 0.5 2 16 SC, IM, by intra-articular injection, or by local venous
Campylobacter jejuni 8 2 8 or intraosseous perfusion in many species.
Escherichia coli 2 4 16
Klebsiella pneumoniae 1 8 8 Clinical Applications
Pasteurella multocida 8 4 Amikacin is a broad-spectrum, bactericidal drug. It is
Proteus spp. 2 16 useful for severe infections in animals, such as Gram-
Pseudomonas aeruginosa 4 negative septicemia caused by gentamicin-resistant
Salmonella spp.